US 2006OOO9478A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0009478 A1 Friedmann et al. (43) Pub. Date: Jan. 12, 2006

(54) METHODS FOR THE TREATMENT OF (60) Provisional application No. 60/511,841, filed on Oct. BACK 15, 2003. Provisional application No. 60/566,189, filed on Apr. 27, 2004. (76) Inventors: Nadav Friedmann, Lafayette, CA (US); Remi Barbier, San Francisco, Publication Classification CA (US); Grant L. Schoenhard, San Carlos, CA (US) (51) Int. Cl. A6IK 31/485 (2006.01) Correspondence Address: (52) U.S. Cl...... 514/282 MCANDREWS HELD & MALLOY, LTD 500 WEST MAIDSON STREET SUTE 3400 CHICAGO, IL 60661 (57) ABSTRACT (21) Appl. No.: 11/089,283 Methods and materials, including novel compositions, dos age forms and methods of administration, useful for treating (22) Filed: Mar. 23, 2005 using opioid antagonists, including combinations Related U.S. Application Data of opioid antagonists and opioid agonists. Methods and materials comprising opioid antagonists or combinations (63) Continuation-in-part of application No. 10/966,703, opioid antagonists and agonists may optionally include one filed on Oct. 15, 2004. or more additional therapeutic agents. Patent Application Publication Jan. 12, 2006 Sheet 1 of 13 US 2006/0009478A1

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Film Coat; Base Coat Opadry Clear Aesthetic Color Coat Opadry II yellow Perforated Coating System Water Water IPC5: Base Coat Application IPC6: Aesthetic Color Coat Application

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METHODS FOR THE TREATMENT OF BACK is largely due to the fact the lower part of the Spine bears the PAN entire weight of the upper body and is bent, twisted and flexed during everyday activities more than any other part of CROSS REFERENCE TO RELATED the Spine. Pain associated with damage to the Supportive Soft APPLICATIONS tissues (muscles, tendons and ligaments), and the interver 0001. This application claims the priority of U.S. Patent tebral disks themselves, is caused by the inflammatory Application No. 60/511,841, filed Oct. 15, 2003 (provi proceSS. sional) and U.S. Patent Application No. 60/566,189, filed 0006 Inflammation arises in connection with many Apr. 27, 2004 (provisional), and is a continuation-in-part of chronic conditions, including, for example, arthritic condi U.S. patent application Ser. No. 10/966,703, filed Oct. 15, tions Such as osteoarthritis (OA). Osteoarthritis is a degen 2004 (nonprovisional). The applications cited above are erative joint disease, characterized by the breakdown of the hereby incorporated by reference in their entirety. joint's cartilage. Cartilage breakdown causes bones to rub against each other, causing pain and/or loSS of movement. FIELD OF THE INVENTION Osteoarthritis can range from very mild to very Severe and 0002 The present invention relates to methods and mate can affect the back, the , the hands and weight-bearing rials useful for the treatment of back pain, including low joints Such as knees, hips, and feet. back pain, using opioid antagonists, including combinations 0007 Another chronic condition with which inflamma of opioid antagonists and opioid agonists. The methods and tion is associated is rheumatoid arthritis (RA). Rheumatoid materials provide human Subjects with an alleviation of back arthritis involves inflammation in the lining of the joints pain and with an attenuation of one or more adverse effects, and/or other internal organs. Rheumatoid arthritis typically including withdrawal, dependence, tolerance, or addiction. affects many different joints. It is typically chronic, but can The methods and materials additionally or alternatively be a disease of flare-ups. Rheumatoid arthritis is a Systemic provide human Subjects with an alleviation of back pain and disease that affects the entire body including the back and is with an attenuation of one or more opioid-related adverse one of the most common forms of arthritis. effects Such as pruritis, Somnolence or constipation. Meth 0008 Another chronic condition with which inflamma ods and materials comprising opioid antagonists or combi tion is associated is back pain, particularly lower back pain. nations of opioid antagonists and agonists are provided and Lower back pain affects approximately two-thirds of the may optionally include one or more additional therapeutic U.S. adult population, leads to significant increases in phy agents. Sician office Visits, and has a significant effect on disability. BACKGROUND OF THE INVENTION 0009. Oxycodone, morphine and oxymorphone have been used in clinical Studies of patients with chronic back 0003) Approximately one in six U.S. adults (16%) suf pain. Oxycodone controlled release and oxycodone imme fered from back pain every Single day during the preceding diate release compositions have been used in clinical Studies month, according to a recent national Survey by the North of patients with Stable, chronic moderate-to-Severe low back American Spine Society (NASS). NASS also stated that pain as described by Hale et al., Clin. J. Pain, 15, 179-183 eighty percent of adults will Suffer from back pain at Some (1999). A morphine sulfate extended-release product iden point during their lives, and people from back pain tified as AVINZACR (Ligand Pharmaceuticals Incorporated, are dealing with the issue an average of 14 days per month. San Diego, Calif., USA) has been approved for once daily According to the Cleveland Clinic Health System, eighty to administration and is indicated for relief of moderate to ninety percent of the population in the United States will Severe pain requiring continuous around-the-clock opioid Suffer from back pain during their lifetime, and back pain is therapy for an extended period of time. An oxymorphone the Second most common reason for doctor Visits. extended release composition has been used in clinical 0004 Back pain can arise from many causes, including Studies of ambulatory patients with moderate-to-Severe disc herniation, Osteoarthritis, , spondylolis chronic as described by Hale et al., Clin. J. thesis, and ankylosing . Back pain can also arise Pain, 6(1), 21-28 (2005). from infection, , fracturem, and nonspinal causes. 0010 Crain and Shen in U.S. Pat. Nos. 5,472,943; 5,512, Low back pain is a very common disorder among adults. 578 reissued as RE 36.457; 5,580,876; 5,767,125; 6,096, Most low back pain is nonspecific; it has no known cause 756; and 6,362,194 as well as U.S. Patent Application and generally cannot be given a precise pathoanatomical Publication No. 20020094947 A1 (the disclosures of which diagnosis. According to Snook, J. Occup Rehabil, are incorporated herein by reference) describe methods and 14(4):243-53 (2004), there are many different treatments for compositions of opioids for Selectively enhancing the anal nonspecific low back pain, but most of them are ineffective. gesic potency of a bimodally-acting opioid agonist and 0005. Many cases of back pain result from weakness of Simultaneously attenuating anti-analgesia, , the back muscles. This includes back pain associated with hyperexcitability, physical dependence and/or tolerance StreSS, when the back muscles often go into Spasm. The effects associated with the administration of the bimodally intervertebral disks are Subjected to different types of StreSS, acting opioid agonist, by administering to a Subject an and degeneration of the disks can give rise to chronic back or Sub-analgesic amount of a bimodally-acting pain as the muscles Supporting the disks go into Spasm. The opioid agonist and an amount of an excitatory opioid recep degenerating disk can itself become inflamed and may cause tor antagonist effective to enhance the analgesic potency of mechanical pain. The lower part of the back (the lumbar the bimodally-acting opioid agonist and attenuate the anti region) is the most Vulnerable area of the back, and lower analgesia, hyperalgesia, hyperexcitability, physical depen back pain is the most common occurrence of back pain. This dence and/or tolerance effects of the bimodally-acting opioid US 2006/0009478 A1 Jan. 12, 2006 agonist. Also disclosed are methods and compositions of 0.015 U.S. Patent Application Publication No. opioids for treating pain in a Subject by administering to the 20030191147 A1 (the disclosure of which is incorporated Subject an analgesic or Sub-analgesic amount of a bimod herein by reference) describes novel dosage forms, pharma ally-acting opioid agonist and an amount of an excitatory ceutical compositions, kits, and methods of administration opioid receptor antagonist effective to enhance the analgesic of an opioid antagonist, including in an amount of at least potency of the bimodally-acting opioid agonist and Simul about 0.0001 mg to about or less than about 1.0 mg, taneously attenuate anti-analgesia, hyperalgesia, hyperexcit including from about 0.0001 mg to less than about 0.5 mg. ability, physical dependence and/or tolerance effects of the Disclosed are Solid oral dosage forms comprising an opioid bimodally-acting opioid agonist. antagonist and another active ingredient, Such as an opioid agonist. Also disclosed are immediate release oral dosage 0011 U.S. Patent Application Publication Nos. forms and concurrent release dosage forms comprising an 20010006967 A1 and 20020094947 A1 (the disclosures of opioid antagonist and another active ingredient. which are incorporated herein by reference) describe a method for Selectively enhancing the analgesic potency of a 0016 Although a variety of therapeutic agents have been bimodally-acting opioid agonist Such as tramadol and Simul used for treating pain and/or inflammation, including taneously attenuating anti-analgesia, hyperalgesia, hyperex and/or inflammation the treatment is often Still citability, physical dependence and/or tolerance effects asso ineffective. In particular, back pain is often poorly managed ciated with the administration of the bimodally-acting opioid or controlled even by the chronic administration of Such agonist. Disclosed are methods and compositions of trama agents. This may be due to the loSS of potency of the agent dol in analgesic or Sub-analgesic amounts and an opioid and/or the development of Side effects associated with antagonist Such as naltrexone or nalmefene. chronic treatment with the agent. 0012 U.S. Patent Application Publication No. SUMMARY OF THE INVENTION 20010018413 A1 and U.S. Pat. No. 6,737,400 (published as U.S. Patent Application No. 20020173466 A1) (the disclo 0017. The present disclosure provides methods for the Sures of which are incorporated herein by reference) treatment of back pain. Methods and materials are described describe a method for treating a subject with irritable bowel which provide human Subjects with alleviation of back pain, syndrome (“IBS”) with an opioid antagonist. Disclosed are including low back pain. Methods and materials are materials and methods for long-term administration of an described which provide treatment for back pain, including opioid receptor antagonist at an appropriately low dose chronic back pain, and including wherein the back pain is which will Selectively antagonize excitatory opioid receptor moderate or Severe. Methods and materials are described functions, but not inhibitory opioid receptor functions, in which comprise opioid antagonists or combinations of myenteric neurons in the intestinal tract as well as in neurons opioid antagonists and agonists and may optionally include of the central nervous system (“CNS”). The administration one or more additional therapeutic agents. of the opioid receptor antagonist at a low dose reduces abdominal pain and Stool frequency. Also disclosed are 0018. In one aspect, the present invention provides meth compositions for treating a Subject with IBS, which com ods for treating back pain in a human Subject comprising prise an effective dose of an opioid receptor antagonist, and administering to the Subject an opioid agonist and an opioid a pharmaceutically acceptable carrier. antagonist wherein back pain is alleviated and wherein the amount of the antagonist or the amount of the agonist and 0013 U.S. Patent Application Publication No. the amount of the antagonist together is effective to attenuate 2002.013776 A1 (the disclosure of which is incorporated withdrawal. herein by reference) describes a method for increasing analgesic potency of a bimodally-acting opioid agonist in a 0019. In another aspect, the present invention provides Subject, by inhibiting GM1-ganglioside in nociceptive neu methods for treating back pain in a human Subject compris rons. The publication describes methods for treating pain, ing administering to the Subject an opioid agonist and an including methods for treating chronic pain, in a Subject in opioid antagonist, wherein back pain is alleviated and need of treatment thereof. Additionally, a method is wherein the amount of the antagonist is effective to attenuate described for treating tolerance to or an addiction to a one or more of the adverse effects commonly associated with bimodally-acting opioid agonist in a Subject in need of opioids (e.g., opioid-related or opioid associated adverse effects, Such as, for example, skin and Subcutaneous tissue treatment thereof. A pharmaceutical composition of analge disorders (e.g., pruritus), gastrointestinal disorders (e.g., sic agents and a pharmaceutically-acceptable carrier is constipation, nausea, vomiting), nervous System disorders described. (e.g., dizziness, Somnolence), or respiratory depression. 0014) International Publication No. WO 01/085150 0020. In yet another aspect, the present disclosure pro (International PCT/US01/14644) (the disclosure of which is vides methods for treating back pain in a human Subject incorporated herein by reference) describes novel composi comprising administering to the Subject an opioid agonist tions and methods for enhancing potency or reducing adverse side effects of opioid agonists in humans, including and an opioid antagonist, wherein back pain is alleviated and with an opioid agonist and an opioid antagonist to differen wherein the amount of the antagonist or the amount of tially dose a human Subject So as to either enhance analgesic agonist and an amount of antagonist together is effective to potency without attenuating an adverse Side effect of the attenuate one or more adverse effects, Such as tolerance, agonist, or alternatively maintain the analgesic potency of dependence or addiction. the agonist while attenuating an adverse side effect of the 0021. In another aspect, the present invention provides agonist. Also described are novel opioid compositions and methods for treating back pain in a human Subject by methods for the gender-based dosing of men and women. administering to the Subject an opioid antagonist, wherein US 2006/0009478 A1 Jan. 12, 2006 the amount of the antagonist is effective for enhancing the about 160 mg, the amount of the antagonist may be from potency of an opioid agonist to alleviate back pain and for about 0.0001 mg to about 0.004 mg; the amount of the attenuating withdrawal. antagonist may be 0.001 or 0.002 mg or less, 0.0001 mg or 0022. Potency may refer to the strength of a drug or drug 0.0002 mg or less, 0.00001 mg or 0.00002 mg or less, treatment in producing desired effects, for example, including wherein the amount is administered one-time, improved pain relief, improved pain control, reduced Stiff two-times, three-times, or four-times per day, preferably neSS, and/or improved physical function. Potency also may two-times per day; the amount of the agonist may be about refer to the effectiveness or efficacy of a drug treatment in 2.5 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, eliciting desired effects, for example, improved pain relief, about 30 mg, about 40 mg, about 80 mg, about 160 mg, or improved pain control, reduced Stiffness, and/or improved about 320 mg, the amount of the antagonist administered physical function. For example, enhanced potency may refer may be at least about 1250 fold less than the amount of the to the lowering of a dose in achieving desired effects or to agonist administered; the amount of the antagonist admin an increased therapeutic benefit including that not previ istered may be at most about 1,600,000 fold less than the ously Seen. Enhanced potency may be seen where a Subject amount of the agonist administered; the amount of the titrates at a lower dose of opioid agonist, or obtains an antagonist administered to the Subject may be no more than acceptable level of pain relief at a lower dose, wherein the about 80.4 ugs, about 40.2 tugs, about 20 ugs, about 10 ugs, lower dose is a lower daily dose or a lower cumulative dose about 5 ugs, about 2.5 lugs, about 1.2 tugs, about 0.6 ug about over a period. In therapeutics, for example, potency may 0.3 ug or about 0.12 lug; the amount of the antagonist refer to the relative pharmacological activity of a compound administered to the Subject may be at least about 0.0002 ug or a composition. about 0.1 lug about 0.2 ug about 0.4 ug about 0.8 ug about 1.6 lug about 3.3 lig or about 6.6 lug; the amount of the 0023. In another aspect, the present invention provides antagonist administered may be effective to enhance the methods for treating back pain in a human Subject by potency of the agonist for alleviating back pain, including administering to the Subject an opioid antagonist, wherein wherein the enhanced potency is measured by administering the amount of the antagonist is effective for enhancing the a lower dose to achieve alleviation of back pain. potency of the opioid agonist to alleviate back pain and for attenuating one or more opioid-related adverse effects, Such 0027 Novel compositions, dosage forms, kits, and other as, for example, skin and Subcutaneous tissue disorders (e.g., materials are described which comprise an opioid antagonist pruritus), gastrointestinal disorders (e.g., constipation, nau for use in or with the foregoing methods including wherein Sea, vomiting), or nervous system disorders (e.g., dizziness, the amount of the antagonist is effective for attenuating Somnolence), or respiratory depression. withdrawal, or for attenuating one or more opioid-related adverse effects, or for attenuating tolerance, dependence, or 0024. In yet another aspect, the present invention pro addiction, and including compositions, dosage forms, kits, vides methods for treating back pain in a human Subject by and other materials with an opioid agonist and an opioid administering to the Subject an opioid antagonist, wherein antagonist, including wherein the amount of the agonist and the amount of the antagonist is effective for enhancing the the amount of the antagonist together are effective for potency of an opioid agonist to alleviate back pain and for alleviating back pain. attenuating one or more adverse effects, Such as tolerance, dependence, or addiction. 0028. In yet another aspect, the present disclosure pro vides methods and materials for dosing an opioid antagonist 0.025 In yet another aspect, the present invention pro administered to a human Subject having back pain. An vides methods for the treatment of back pain, including amount of an opioid antagonist and an amount of an opioid chronic back pain, and the inflammation associated with the agonist are administered to the Subject, and back pain is back pain. assessed. A level of the opioid antagonist or a Surrogate of 0026. For any of the methods described herein, including the opioid antagonist in a Sample from the Subject is mea the foregoing methods: the back pain may be associated with Sured. The amount of the opioid antagonist or the amount of a neck, upperback, middle back or lower back of the Subject, the opioid agonist to the Subject is adjusted based on the the back pain may be chronic, and/or the back pain may be measured level. moderate or Severe; the agonist, the antagonist, or both the 0029. In another aspect, the present disclosure provides agonist and the antagonist may be administered no more methods and materials for dosing an opioid antagonist than twice in a 24-hour period, or no more than once in a administered to a human Subject having back pain. An 24-hour period; the amount of the antagonist may be 0.004 amount of an opioid antagonist and an amount of an opioid mg or less in a 24-hour period, or 0.002 mg or less in a agonist are administered to the Subject, and back pain is 24-hour period; the antagonist, the agonist, or both the assessed. The amount of the opioid antagonist administered antagonist and the agonist may be administered in an oral to the Subject is adjusted if back pain is not alleviated to a dosage form, including a Solid oral dosage form or a liquid oral dosage form; the agonist may be codeine, hydromor desired extent and/or if one or more adverse effects are not phone, meperidine, morphine, oxycodone, oxymorphone, alleviated to a desired extent. propoxyphene, hydrocodone, pentazocine, fentanyl, Sufen 0030. In another aspect, the present disclosure provides tanyl, methadone, tramadol, or dihydrocodeine; the antago methods and materials for dosing an opioid antagonist nist may be naltrexone, nalmefene, or naloxone; the mode of administered to a human Subject having back pain. An administration of the agonist, the antagonist, or both, may be amount of an opioid antagonist and an amount of an opioid oral, intravenous, intrathecal, epidural, intramuscular, Sub agonist are administered to the Subject, and back pain is cutaneous, perineural, intradermal, topical, or transcutane assessed. A level of the opioid antagonist or a Surrogate of ous, the amount of the agonist may be from about 2.5 mg to the opioid antagonist in a Sample from the Subject is mea US 2006/0009478 A1 Jan. 12, 2006

Sured. The amount of the opioid antagonist administered to of opioid agonist-induced hyperalgesia, prevention of physi the Subject is adjusted if the measured level is outside a (e.g., cal dependence or withdrawal, decreased rewarding/eu above or below) predetermined range. phoric side effect, or decreased potential for relapse/addic 0031. In another aspect, the present disclosure provides tion. methods and materials for determining the amount of an opioid antagonist or opioid agonist to be administered to a BRIEF DESCRIPTION OF THE FIGURES human Subject and back pain is assessed. A level of the 0036 FIG. 1 shows plasma concentrations (meani-SEM) opioid antagonist or a Surrogate of the opioid antagonist in of oxycodone (ng/mL) in the three treatment groups from a Sample obtained from the human Subject is measured. For the clinical Study conducted as described in Example 1: example, the level of 6f-naltrexol can be measured as a oxycodone QID represented as red circles (o); the combi Surrogate. The 6?-naltrexol level (e.g., the concentration of nation drug of oxycodone and naltrexone QID represented 6?-naltrexol in a plasma sample) can be a Surrogate marker as green triangles (A); and the combination drug of oxyc for assessing back pain. On the basis of the measured level, odone and naltrexone BID represented as pink Squares (D). the amount of the opioid antagonist or the amount of the opioid agonist for administration to the human Subject is 0037 FIG. 2 shows plasma concentrations (meani-SEM) adjusted. of oxymorphone (ng/mL) in the three treatment groups from the clinical Study conducted as described in Example 1: 0032. In another aspect, the present disclosure provides Oxycodone QID represented as the bar having diagonal methods and materials for reducing the level of a biomarker lines, the combination drug of oxycodone and naltrexone in a human Subject having back pain wherein a composition QID represented as the bar having diamonds, the combina comprising an opioid antagonist and optionally an opioid tion drug of oxycodone and naltrexone BID represented as agonist is administered to the human Subject. the darker bar having polka dots. 0033. In yet another aspect, the present disclosure pro 0038 FIG. 3 shows plasma concentrations vides methods and materials for monitoring the response of (median-Equartiles) of oxycodone (ng/mL) after the final a human Subject being treated for back pain by administer dose in the three treatment groups from the clinical Study ing an opioid antagonist and optionally an opioid agonist. conducted as described in Example 1. The level of one or more one biomarker(s) in a first sample from the subject is determined prior to treatment with the 0039 FIG. 4 shows log-transformed plasma concentra opioid antagonist and optionally the opioid agonist. The tions (mediant(quartiles) of oxycodone after the final dose in level of the biomarker in at least a Second Sample from the the three treatment groups from the clinical Study conducted Subject is determined Subsequent to the initial treatment with as described in Example 1. the opioid antagonist and optionally the opioid agonist. The 0040 FIG. 5 shows log-transformed plasma concentra level of the biomarker in the Second Sample is compared tions (median-Equartiles) of oxymorphone after the final dose with the level of the biomarker in the first sample. A change in the three treatment groups from the clinical Study con in the level of the biomarker in the Second Sample compared ducted as described in Example 1. to the level of the biomarker in the first sample indicates the 0041 FIG. 6 shows dose-normalized plasma concentra effectiveness of the treatment. tions (meani-SEM) of oxycodone (ng/mL) in the three 0034 Novel compositions, dosage forms, kits, and other treatment groups from the clinical Study conducted as materials are described which comprise an opioid antagonist described in Example 1: Oxycodone QID represented as red for use in or with the foregoing methods including wherein circles (o); the combination drug of oxycodone and naltr the amount of the antagonist is effective for enhancing the exone QID represented as green triangles (A); and the potency of an opioid agonist for alleviating back pain, and combination drug of oxycodone and naltrexone BID repre including compositions, dosage forms, kits, and other mate Sented as pink Squares (D). rials with an opioid agonist and an opioid antagonist, includ ing wherein the amount of the agonist and the amount of the 0042 FIG. 7 shows plasma concentrations (meani-SEM) antagonist together are effective for alleviating back pain. of 6f-naltrexol (ug/mL) for two of the treatment groups from the clinical Study conducted as described in Example 0.035 Thus, the present disclosure provides methods and 1: the combination drug of oxycodone and naltrexone QID materials comprising opioid antagonists, including opioid represented as the bar having diamonds, the combination agonists and antagonists, that provide pain relief (including drug of oxycodone and naltrexone BID represented as the enhanced potency of the opioid agonist), with an improve darker bar having dots. ment in Side effect profile, even with chronic administration including as compared with methods and materials without 0043 FIG. 8 shows efficacy measures versus oxycodone opioid antagonists. Advantages of methods and materials of concentrations after the final dose for the three treatment the disclosure include enhanced and prolonged analgesia, from the clinical Study conducted as described in Example attenuation of one or more adverse effects, including, for 1: Oxycodone QID represented as black circles, the combi example, opioid-related adverse effects, Such as, for nation drug of oxycodone and naltrexone BID represented as example, skin or Subcutaneous tissue disorders (e.g., pruri red Squares, the combination drug of oxycodone and naltr tus), or including, for example, one or more adverse effects eXOne QID represented as green diamonds. Selected from withdrawal, dependence, tolerance, or addic 0044 FIG. 9 shows efficacy measures versus oxymor tion. Additional advantages include, for example, attenua phone concentrations after the final dose for the three tion of one or more Symptoms or signs of withdrawal or treatment groups from the clinical Study conducted as dependence, prevention of tolerance or continued protection described in Example 1: Oxycodone QID represented as against tolerance even with chronic administration, reversal black circles, the combination drug of oxycodone and nal US 2006/0009478 A1 Jan. 12, 2006 trexone BID represented as red Squares, the combination 0053 Chronic back pain is pain that persists beyond drug of oxycodone and naltrexone QID represented as green acute pain, for example for more than 3 months, or beyond diamonds. the time that normal healing occurs. It is often progressive 004.5 FIG. 10 shows efficacy measures versus 6B-naltr and the cause can be difficult to determine. Chronic back exol concentrations after the final dose for two of the pain can include pain from or associated with cancer. Acute treatment groups from the clinical Study conducted as or short-term low back pain generally lasts from a few days described in Example 1: the combination drug of oxycodone to a few weeks. Acute or chronic back pain may be the result and naltrexone BID represented as black circles, the com of Surgery, including failed back Surgery, or trauma, for bination drug of oxycodone and naltrexone QID represented example, trauma to the lower back or the result of a disorder as red Squares. Such as arthritis. Acute or chronic pain may be the result of 0.046 FIG. 11 shows the percent change in pain intensity pathogenic mechanisms that are nociceptive, neuropathic or reported by some of the subjects in Table 23 vs. 6B-maltrexol mixed in origin. Often, however, the acute or chronic back plasma concentrations measured for those Subjects, as pain has no known cause. described in Example 3. 0054 Back pain can be described as radicular back pain, 0047 FIG. 12 shows the percent change in pain intensity which involves an inflamed nerve root, and referred back pain, which involves a musculoskeletal sprain or . reported by subjects in Table 23 who received the BID Neuropathic back pain generally involves damage to nerve dosing regimen VS. 6(3-maltrexol plasma concentrations mea tissue. Nociceptive back pain generally involves an injury or Sured for those Subjects as described in Example 3. disease outside the nervous System. Some people experience 0.048 FIG. 13 shows steps in a process for the prepara mixed pain, which is a combination of neuropathic and tion of dosage forms of opioid agonist and opioid antagonist. nociceptive back pain. Mechanical back pain is aggravated DETAILED DESCRIPTION OF THE by movement and worsened by coughing. Mechanical back INVENTION pain is typical of a herniated disc or StreSS fracture. For 0049. The present disclosure provides methods and mate patients with this condition, forward movements of the Spine rials, including novel compositions, dosage forms and meth usually cause pain. In addition, posture, coughing, Sneezing, ods of administration, useful for the treatment of back pain and movement can all influence pain coming from the Spine. using opioid antagonists, including combinations of opioid When acute back pain is Severe and travels down both legs, antagonists and opioid agonists. The methods and materials it could be caused by lumbar disc disease. Back pain also provide human Subjects with alleviation of back pain and includes Sciatic back pain (or ). Sciatica refers to pain attenuation of one or more adverse effects of the opioid that begins in the hip and buttockS and continues down the agonist. The back pain may be chronic back pain. The back leg. The term Sciatica generally indicates that the Sciatic pain may be moderate or Severe. The back pain may be nerve, which travels from the lower back through the nociceptive, neuropathic or mixed in origin. The methods buttocks and into the leg, is thought to be the cause of the and materials alleviate back pain and attenuate (e.g., ame pain in this condition. True Sciatica is a condition that occurs liorate, alleviate, reduce, diminish, block, inhibit or prevent) when a herniated lumbar disc compresses one of the con one or more adverse effects Selected from withdrawal, tributing roots of the Sciatic nerve. dependence, tolerance or addiction. The methods and mate 0055 Back pain can arise from many different causes, rials alleviate back pain and attenuate (e.g., ameliorate, Such as muscle Strains or other muscle injury or disease, alleviate, reduce, diminish, block, inhibit or prevent) one or rupture or other damage to one or more discS, Spinal more opioid-related adverse effects, Such as, for example, Stenosis, arthritis, , and . skin and Subcutaneous tissue disorders (e.g., pruritus), gas Muscle Strains are a common cause of low back pain. A trointestinal disorders (e.g., constipation, nausea, vomiting), ruptured , also called a herniated disc, is or nervous System disorders (e.g., dizziness, Somnolence). another common cause of back pain. Discogenic back pain Methods and materials provided comprise opioid antago is thought to be a common cause of low back pain. Disco nists, including combinations opioid antagonists and ago genic back pain is the result of damage to the intervertabral nists and may optionally include one or more additional disc, but without disc herniation. Spinal Stenosis refers to therapeutic agents. constriction of the Spinal canal as people age. It may be due 0050. The present methods and materials are useful for in part to arthritis and other conditions. If the Spinal canal the treatment of back pain, including but not limited to becomes too tight, back pain can be the result. Arthritis can chronic back pain, acute back pain, low back pain, acute low affect any joint in the body, including the Small joints of the back pain, chronic low back pain, , upper back Spine. Arthritis of the Spine can cause back pain with pain, middle back pain, cancerous back pain, non-cancerous movement. Spondylolisthesis can cause back pain because back pain, arthritic back pain, non-arthritic back pain, noci adjacent become unstable and begin to “slip.” The ceptive back pain, neuropathic back pain, radicular back most common cause of Spondylolisthesis is due to degen pain, referred back pain, mechanical back pain, and Sciatic erative changes causing loSS of the normal Stabilizing Struc back pain. tures of the Spinal column. Osteoporosis can cause a number 0051. The present methods and materials are useful for of orthopedic problems and generalized discomfort. Back the treatment of inflammation associated with a chronic pain from Osteoporosis is most commonly related to com condition, including chronic back pain. pression fractures of the Vertebra. Osteoporosis causes weak 0.052 The present methods and materials are useful for bones and can lead to these fractures. the treatment of back pain, including chronic back pain that 0056 Back pain can originate from spinal compression, is associated with or mediated by the peripheral or central degeneration or injury, muscle trauma or irritation, or nervous System. another non-traumatic event. Low back pain can also begin US 2006/0009478 A1 Jan. 12, 2006 in other regions of the body and eventually attack the development of a new anxiety disorder related to drug use, muscles or other Structures in the lower back. Sometimes or due to true withdrawal Symptoms. low back pain can even begin in the nerves or nervous System. Other origins for low back pain are Surgery, post 0061 Tolerance may occur to both the desired and undes neural difficulties, congenital disorders, trauma, infections, ired effects of drugs, and may develop at different rates for degenerative disorders, inflammatory diseases, circulatory different effects. For example, in the case of opioids, toler disorders, failed Surgery, or other causes. ance usually develops more slowly to analgesia than to respiratory depression, and tolerance to the constipating 0057 Back pain can result from nerve or muscle irrita effects may not occur at all. Tolerance to the analgesic tion, bone lesions, or other causes. Most low back pain follows injury or trauma to the back, but pain may also be effects of opioids is considered to be an undesirable or caused by degenerative conditions Such as arthritis or disc adverse effect. It is variable in occurrence but is not gener disease, osteoporosis or other bone diseases, Viral infections, ally absolute; thus, no upper limit to dosage of pure opioid irritation to joints and discs, or congenital abnormalities in agonists can be established. the Spine. Obesity, Smoking, weight gain during pregnancy, 0062 Symptoms and signs of withdrawal include hype StreSS, poor physical condition, posture inappropriate for the ralgesia, increased rate, increased respiratory rate, or activity being performed, and poor Sleeping position also increased pupilary diameter. Symptoms and Signs of with may contribute to low back pain. Additionally, Scar tissue drawal also include muscle cramps, yawning, upset Stom created when the injured back heals itself does not have the ach, runny nose, watery eyes, abdominal cramps, chills/ strength or flexibility of normal tissue. Buildup of scar tissue gooseflesh, or clammy/damp skin, all of which can be from repeated injuries eventually weakens the back and can determined measured objectively by a trained observer lead to more Serious injury. and/or Subjectively by the human Subject. Symptoms and 0.058 As discussed in detail herein, back pain can be signs of withdrawal also include symptoms of the Short alleviated using opioid agonists. The present methods and Opiate Withdrawal Scale, namely the symptoms of feeling materials comprise opioid antagonists and are useful for the sick, Stomach cramps, muscle Spasms/twitching, feelings of treatment of back pain and provide human Subjects with coldness, heart pounding, muscular tension, aches and , alleviation of back pain and attenuation of one or more yawning, runny eyes, or insomnia/problems sleeping (e.g., adverse effects, Such as withdrawal, dependence, tolerance insomnia and/or problems sleeping). The SOWS assessment or addiction. is described in Gossop, “The Development of a Short Opiate Withdrawal Scale (SOWS).” Addictive Behaviors, Vol. 15, 0059 Adverse effects of opioids can include withdrawal, p. 487-490, 1990 (incorporated by reference herein), which dependence, tolerance or addiction. Physical dependence, states “The scale has shown criterion validity in that the tolerance and addiction have been defined by the American Scores are elevated during the acute phase of withdrawal and Academy of Pain Medicine, the American Pain Society, and gradually return to normal, baseline after levels after detoxi the American Society of Addiction Medicine. American Pain fication, and good discriminative efficiency is shown by the Society, “Definitions Related to the Use of Opioids for the Scale's capacity to differentiate between addicts during Treatment of Pain” (2001). Physical dependence is withdrawal phase and post withdrawal.” described as a State of adaptation that is manifested by a drug class specific withdrawal Syndrome that can be produced by 0063 Attenuation of withdrawal can be measured by abrupt cessation, rapid dose reduction, decreasing blood attenuation of hyperalgesia, increased heart rate, increased level of the drug, and/or administration of an antagonist. respiratory rate, increased pupilary diameter, muscle Tolerance is described as a State of adaptation in which cramps, yawning, upset Stomach, runny nose, Watery eyes, exposure to a drug induces changes that result in a diminu abdominal cramps, chills/gooseflesh, or clammy/damp skin. tion of one or more of the drug's effects over time. Addiction Attenuation of withdrawal can also be measured on the is described as a primary, chronic, neurobiologic disease, Short Opiate Withdrawal Scale (SOWS). Attenuation of with genetic, psychoSocial, and environmental factions withdrawal can also be measured by attenuation of one or influencing its development and manifestations. It is char more of the symptoms of the Short Opiate Withdrawal Scale, acterized by behaviors that include one or more of the namely the Symptoms of feeling Sick, Stomach cramps, following: impaired control over drug use, compulsive use, muscle Spasms/twitching, feelings of coldness, heart pound continued use despite harm, and craving. ing, muscular tension, aches and pains, yawning, runny eyes, or insomnia/problems Sleeping. 0060 Physical dependence on and/or tolerance to pre Scribed drugs are predicatable adverse effects that often 0064. Attenuation of withdrawal indicates attenuation of occur with the persistent use of certain medications, Such as physical dependence, Since lesser withdrawal indicates opioids. Physical dependence may develop with chronic use lesser physical dependence. Symptoms and Signs of physical of many classes of medications. When drugs that induce dependence on an opioid include the Symptoms and Signs of physical dependence are no longer needed, they should be withdrawal when the patient discontinues taking the opioid. carefully tapered while monitoring clinical Symptoms to Another Symptom or Sign of physical dependence is the avoid withdrawal phenomena and Such effects as rebound production of an abstinence Syndrome, or its Symptoms or hyperalgesia. At times, anxiety and Sweating can be seen in Signs, by the administration of a Sufficiently high dose of patients who are dependent on Sedative drugs, Such as opioid antagonist. Symptoms and Signs of an abstinence alcohol or benzodiazepines, and who continue taking these Syndrome include anxiety, irritability, chills and hot flashes, drugs. This is usually an indication of development of joint pain, Salivation, lacrimation, rhinorrhea, diaphoresis, tolerance, though the Symptoms may be due to a return of the piloerection, nausea, vomiting, abdominal cramps, diarrhea, Symptoms of an underlying anxiety disorder, due to the or sleep disturbances/insomnia. US 2006/0009478 A1 Jan. 12, 2006

0065 Symptoms and signs of tolerance include a need to pain refers to an amount of opioid antagonist or combination increase dose to maintain pain relief, a decrease in duration of opioid agonist and antagonist with or without one or more of pain relief for a given dose, anxiety, or Sweating. additional therapeutic agents which elicits alleviation (e.g., 0.066 Symptoms and signs of addiction include impaired amelioration, attenuation, reduction, diminishment, block control over opioid agonist, compulsive use of opioid ago age, inhibition or prevention) of back pain upon adminis nist, continued use of opioid agonist despite harm to the tration to a Subject (e.g., patient) in need thereof. The Subject, or craving of opioid agonist. amount of the opioid agonist, the opioid antagonist, or 0067. The present disclosure provides methods and mate another therapeutic agent can refer to the weight of the Salt rials for alleviating back pain and attenuating one or more of or the weight of the free base of Such agonist, antagonist or the adverse effects and/or Symptoms or Signs of the adverse agent. effects described above. The present disclosure provides 0072 An amount of opioid antagonist that enhances the methods and materials for treating back pain by adminis potency of an opioid agonist to alleviate back pain, is the tering to a human Subject with back pain an opioid antago amount that when added to an analgesic or Subanalgesic nist or an opioid agonist with an opioid antagonist. Methods amount of agonist results upon administration in a greater and materials provided are effective for the treatment of back alleviation (e.g., amelioration, attenuation, reduction, dimin pain, including chronic back pain, with attenuation of ishment, blockage, inhibition or prevention) of back pain, adverse effects. Methods and materials provided are effec than the alleviation of back pain resulting from administra tive for the treatment of moderate, moderate-to-Severe back tion of that agonist alone (i.e., without that amount of pain or Severe back pain. For example, the amount of an antagonist). opioid antagonist is an amount effective for maintaining or enhancing the potency of an opioid agonist for alleviating 0073. An amount of opioid antagonist that enhances the the back pain. The pain intensity is thereby alleviated (e.g., potency of an endogenous opioid agonist is the amount that ameliorated, attenuated, reduced, diminished, blocked, when administered alone or with opioid agonist or another inhibited or prevented). therapeutic agent, results in a greater alleviation (e.g., ame 0068 The present methods and materials are effective for lioration, attenuation, reduction, diminishment, blockage, the treatment of chronic back pain. In the present methods inhibition or prevention) of at least one sign or Symptom of and materials, the antagonist, the agonist, or both the antago pain than the alleviation of that Sign or Symptom without that nist and the agonist can be administered chronically. For amount of antagonist. example, the antagonist, the agonist, or both the antagonist 0074. In the compositions for use in methods according and the agonist can be administered for at least Six weeks, to the present disclosure, the agonist may be present in its for at least twelve weeks, or for a longer period. original form or in the form of a pharmaceutically accept 0069. In the treatment of back pain, including chronic able Salt. The agonists for use in methods according to the back pain, back pain from inflammation associated with a present disclosure include: alfentanil, allylprodine, chronic condition, or back pain associated with an arthritic alphaprodine, anilleridine, apomorphine, apocodeine, ben condition, the antagonist, the agonist, or both the opioid Zylmorphine, beZitramide, butorphanol, clonitaZene, agonist and the opioid antagonist can be administered for at codeine, cyclazocine, cyclorphen, cyprenorphine, desomor least one week, alternatively for at least two weeks, for at phine, dextromoramide, dezocine, diampromide, dihydroco least three weeks, for at least Six weeks, for at least twelve deine, dihydromorphine, dimenoxadol, dimepheptanol, dim weeks, or for a longer period. The antagonist, the agonist, or ethylthiambutene, dioxyaphetyl butyrate, dipipanone, both the opioid agonist and the opioid antagonist can be eptazocine, ethoheptazine, ethylmethylthiambutene, ethyl administered at least once daily for at least one week, morphine, etonitaZene, fentanyl, heroin, hydrocodone, alternatively two weeks, alternatively three weeks, alterna hydroxymethylmorphinan, hydromorphone, hydroxypethi tively six weeks, alternatively twelve weeks, alternatively dine, isomethadone, ketobemidone, levallorphan, levorpha chronically. nol, levophenacylmorphan, lofentanil, meperidine, meptazi nol, metazocine, methadone, methylmorphine, metopon, 0070 The method for treating back pain, including morphine, myrophine, narceline, nicomorphine, norlevor chronic back pain, or back pain from inflammation associ phanol, normethadone, nalorphine, normorphine, norpi ated with a chronic condition, or back pain associated with panone, ohmefentanyl, opium, oxycodone, oxymorphone, an arthritic condition, may comprise administering the papaveretum, phenadoxone, phenomorphan, phenazocine, opioid antagonist or each of the opioid agonist and the phenoperidine, pholcodine, piminodine, piritramide, proph opioid antagonist no more than twice daily for at least one eptazine, promedol, profadol, properidine, propiram, pro week, alternatively two weeks, alternatively three weeks, poxyphene, remifentanyl, Sufentanyl, tramadol, tilidine, alternatively six weeks, alternatively twelve weeks, alterna Salts thereof, mixtures of any of the foregoing, mixed tively chronically. In the treatment of back pain, an opioid mu-agonists/antagonists, mu-antagonist combinations, or agonist, an opioid antagonist, or the combination of an others known to those skilled in the art. Preferred agonists opioid agonist and an opioid antagonist can each be admin for use in methods according to the present disclosure are istered at least once daily or twice daily, alternatively no morphine, hydrocodone, oxycodone, codeine, fentanyl (and more than twice daily. The method for treating back pain its relatives), hydromorphone, meperidine, methadone, oxy may comprise administering to the Subject a daily amount of morphone, propoxyphene or tramadol, or mixtures thereof. the opioid antagonist that is 0.004 mg or less, alternatively Particularly preferred contemplated agonists are morphine, 0.002 mg or less. hydrocodone, oxycodone or tramadol. Opioid agonists 0071 An effective amount to alleviate (e.g., ameliorate, include exogenous or endogenous opioids. Endogenous attenuate, reduce, diminish, block, inhibit or prevent) back opioid agonists include endorphin, beta-endorphin, US 2006/0009478 A1 Jan. 12, 2006 enkephalin, met-enkephalin, dynorphin, orphanin FO, neu 0081 Morphine Sulfate: 1 mg, 2.5 mg, 5 mg, 7.5 mg, 10 ropeptide FF, nociceptin, endomorphin, endormorphin-1, mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, 80 mg, 160 mg, endormorphin-2. and 320 mg. For example, an oral dose of morphine of 30 mg 0075. The agonist may be present in an amount that is (q3-4 hrs) is an approximately equianalgesic oral dose of 30 analgesic or Subanalgesic (e.g., non-analgesic) in the human mg (q3-4 hr) of oxycodone. Subject. The agonist is administered in dosage forms con 0082) Methadone HCl: 0.333 mg, 0.8325 mg, 1.665 mg, taining from about 0.1 to about 300 mg of agonist, alterna 2.4975 mg, 3.33 mg, 4.995 mg., 6.66 mg, 9.09 mg, 13.32 mg, tively from about 2.5 to about 160 mg of agonist. For 19.98 mg, 26.64 mg, 53.28 mg, and 106.56 mg. For example, an agonist (including but not limited to oxyc example, an oral dose of methadone of 20 mg (q3-4 hrs) is odone) can be administered in dosage forms containing an approximately equianalgesic oral dose of 30 mg (q3-4 hr) about 1 mg, alternatively about 2.5 mg, alternatively about of oxycodone. 5 mg, alternatively about 7.5 mg, alternatively about 10 mg, alternatively about 15 mg, alternatively about 20 mg, alter 0083) Levorphanol Tartrate: 0.065 mg, 0.1625 mg, 0.325 natively about 30 mg, alternatively about 40 mg, alterna mg, 0.4875 mg, 0.065 mg, 0.975 mg, 1.3 mg, 1.95 mg, 2.6 tively about 60 mg, alternatively about 80 mg, alternatively mg, 3.9 mg, 5.2 mg, 10.4 mg, and 20.8 mg. For example, an about 5 mg, alternatively about 160 mg, alternatively about oral dose of levorphanol of 4 mg (q3-4 hrs) is an approxi 320 mg of opioid agonist. Alternatively, the agonist can be mately equianalgesic oral dose of 30 mg (q3-4 hr) of administered in dosage forms containing a dose of opioid Oxycodone. agonist that is equivalent to the foregoing doses of oxyc 0084) Hydromorphone HCl: 0.25 mg, 0.625 mg, 1.25 mg, odone hydrochloride. Equivalent doses of one opioid agonist 1.875 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, (Such as morphine, hydromorphone, fertanyl, or others can 20 mg, 40 mg, and 80 mg. For example, an oral dose of be easily calculated from a Stated dose of another opioid hydromorphone of 7.5 mg (q3-4 hrs) is an approximately agonist (Such as oxycodone) using a conversion factor. For equianalgesic oral dose of 30 mg (q3-4 hr) of oxycodone. example, conversion factors are available from the Ameri can Pain Society's website http://www.talaria.org/ 0085 Butorphanol tartrate: 0.1 mg, 0.25 mg, 0.5 mg, 0.75 calculator J20.html as Drug Conversion Calculator Version mg, 1 mg, 1.5 mg, 2 mg, 3 mg, 4 mg, 6 mg, 8 mg, 16 mg, 2.0, from the PDR Electronic Library (2002), and from and 32 mg. Goodman and Gilman, Supra (see, e.g., Tables 23.6 at page 606 of 10" Edition. The Opioid Conversion Chart set forth 0.086 Pentazocine HCl: 8.35 mg, 20.875 mg, 41.75 mg, in Example 6 below can also be used to determine an 62.625 mg, 83.5 mg, 125.25 mg, 167 mg, 250.5 mg, 334 mg. equivalent dose of an opioid agonist based on a Stated dose 501 mg, 668 mg, 1336 mg, and 2672 mg. of another opioid agonist. For example, where dose amounts 0087 Fentanyl: transdermal doses of 0.025 mg/hr, 0.05 of oxycocodone hydrochloride are Set forth in the present mg/hr, 0.075 mg/hr, and 0.100 mg/hr. A transdermal dose of disclSOSure, an equianalgesic dose amount of another opioid fentanyl (e.g., DURAGESIC(R) of 0.025 mg/hr, 0.050 agonist may be used. For example, for dose amounts of mg/hr, 0.075 mg/hr, 0.100 mg/hr, 0.125 mg/hr, 0.150 mg/hr, Oxycodone Such as 1 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 0.175 mg/hr, 0.20 mg/hr, 0.225 mg/hr, 0.250 mg/hr, 0.275 mg, 20 mg, 30 mg, 40 mg, 60 mg, 80 mg, 160 mg, and 320 mg/hr, or 0.300 mg/hr are equivalent to an oxycodone dose mg, the following dose amounts of the following opioid of 45-134 mg/day, 135-224 mg/day, 225-314 mg/day, 315 agonists may be used: 404 mg/day, 405-494 mg/day, 495-584 mg/day, 585-674 0.076 Codeine Phosphate: 6 mg, 15 mg, 30 mg, 45 mg, 60 mg/day, 675-764 mg/day, 765-854 mg/day, 855-944 mg/day, mg, 90 mg, 120 mg, 180 mg, 240 mg, 360 mg, 480 mg,960 945-1034 mg/day, or 1035-1124 mg/day, respectively. mg, and 1920 mg. For example, an oral dose of codeine of 0088. The agonist, in conjunction with antagonist, is 130 mg (q3-4 hr) is an approximate equianalgesic oral dose included in the dosage form in an amount Sufficient to of 30 mg (q-3-4 hr) of oxycodone. produce the desired effect upon the proceSS or condition of 0.077 Hydrocodone Bitartrate: 1 mg, 2.5 mg, 5 mg, 7.5 pain, including inflammatory pain, Such as alleviation (e.g., mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, 80 mg, 160 amelioration, attenuation, reduction, diminishment, block mg, and 320 mg. For example, an oral dose of hydrocodone age, inhibition or prevention) of at least one symptom of of 30 mg (q3-4 hrs) is an approximately equianalgesic oral pain, including inflammatory pain. Symptoms and Signs dose of 30 mg (q3-4 hr) of oxycodone. include, for example, pain (including chronic pain), Stiffness 0078 Propoxyphene HCl: 9 mg, 22.5 mg, 45 mg, 67.5 or difficulty in physical function. mg, 90 mg, 135 mg, 180 mg, 270 mg, 360 mg, 540 mg, 720 0089 Preferred opioid agonists for the present methods mg, 1440 mg, and 2880 mg. For example, an oral dose of and compositions treating back pain include codeine, hydro propoxyphene of 130 mg (q3-4 hrs) is an approximately morphone, meperidine, morphine, oxycodone, oxymor equianalgesic oral dose of 30 mg (q3-4 hr) of oxycodone. phone, propoxyphene, hydrocodone, pentazocine, fentanyl, 0079 Propoxyphene Napsylate: 15 mg, 37.5 mg, 75 mg, Sufentanyl, methadone, tramadol, and dihydrocodeine. 112.5 mg, 150 mg, 225 mg, 300 mg, 450 mg, 600 mg, 900 0090 Preferred combinations of an opioid antagonist and mg, 1200 mg, 2400 mg, and 4800 mg. opioid agonist in the present compositions are naltrexone 0080 Meperidine HCl: 15 mg, 37.5 mg, 75 mg, 112.5 and oxycodone, naltrexone and oxymorphone, naltrexone mg, 150 mg, 225 mg, 300 mg, 450 mg, 600 mg, 900 mg, and hydrocodone, naltrexone and hydromorphone, naltrex 1200 mg, 2400 mg, and 4800 mg. For example, an oral dose one and morphine, nalmefene and oxycodone; nalmefene of meperidine of 300 mg (q3-4 hrs) is an approximately and oxymorphone, nalmefene and hydrocodone; nalmefene equianalgesic oral dose of 30 mg (q3-4 hr) of oxycodone. and hydromorphone, nalmefene and morphine; naloxone US 2006/0009478 A1 Jan. 12, 2006

and oxycodone; naloxone and oxymorphone, naloxone and ate the chronic pain. Chronic pain may result from various hydrocodone, naloxone and hydromorphone, and naloxone abnormal or compromised States (e.g., diseased), including and morphine, respectively. but not limited to Osteoarthritis, rheumatoid arthritis, psori 0.091 The more preferred combinations of an opioid atic arthritis, back pain, cancer, injury or trauma. antagonist and opioid agonist in the present compositions 0098. One or more symptoms and signs of arthritic are naltrexone and Oxycodone; naltrexone and oxymor conditions, inflammation associated chronic conditions or phone, naltrexone and hydrocodone; naltrexone and hydro chronic pain are alleviated (e.g., ameliorated, attenuated, morphone, naltrexone and morphine, nalmefene and oxyc reduced, diminished, blocked, inhibited or prevented), by odone; nalmefene and oxymorphone, nalmefene and the present methods and materials, for example, as measured hydrocodone, nalmefene and hydromorphone, and by an alleviation (e.g., amelioration, attenuation, reduction, nalmefene and morphine, respectively. diminishment, blockage, inhibition or prevention) of pain, 0092. The most preferred combinations of an opioid Stiffness, or difficulty in physical function. antagonist and opioid agonist in the present compositions 0099 Symptoms and signs of arthritic conditions and are naltrexone and Oxycodone; naltrexone and oxymor inflammation resulting from chronic conditions, are allevi phone, naltrexone and hydrocodone; naltrexone and hydro ated (e.g., ameliorated, attenuated, reduced, diminished, morphone; and naltrexone and morphine, respectively. blocked, inhibited or prevented), by the present methods and 0093. The present disclosure also provides methods and materials, for example, as measured by an alleviation (e.g., materials, including novel compositions, dosage forms and amelioration, attenuation, reduction, diminishment, block methods of administration, useful for the treatment of back age, inhibition or prevention) of pain, Stiffness, and/or pain, including where the back pain is from, arthritic con difficulty in physical function. ditions, inflammation associated with a chronic condition or 0100 Thus, the present disclosure provides methods and chronic pain, using opioid antagonists, including combina materials comprising opioid antagonists, including opioid tions of opioid antagonists and opioid agonists. The present agonists and antagonists, that provide greater pain relief, methods and materials provide human Subjects with allevia better pain control, improved function, with no change in tion of one or more Symptoms or signs of the arthritic Side effect profile, even with chronic administration includ condition, inflammation associated with a chronic condition ing as compared with methods and materials without opioid or chronic pain, including, for example, alleviation of pain, antagonists. Advantages of the present methods and mate alleviation of stiffness and/or improvement of physical func rials include enhanced and prolonged analgesia, prevention tion. The present methods and materials comprise opioid of tolerance and continued protection against tolerance even antagonists or combinations of opioid antagonists and ago with chronic administration, reversal of opioid agonists nists may optionally include one or more additional thera induced hyperalgesia, prevention of physical dependence or peutic agents. withdrawal, decreased rewarding/euphoric Side effect, and/ 0094. In one aspect, the amount of the antagonist is or decreased potential for relapse/addiction. effective for enhancing the potency of an opioid agonist for 0101 The present disclosure provides methods and mate alleviating one or more Symptoms or signs associated with rials for treating back pain, including back pain from the arthritic condition inflammation, or chronic condition, or arthritic conditions and/or inflammation associated with the amount of the agonist and the amount of the antagonist chronic conditions in a human Subject by administering to together are effective for alleviating one or more Symptoms the Subject an opioid antagonist or an opioid agonist with an or Signs associated with the arthritic condition, inflamma opioid antagonist. For example, the amount of an opioid tion, or chronic condition. antagonist is effective to enhance the potency of an opioid 0.095. In another aspect, the amount of the antagonist is agonist for alleviating one or more Symptoms or signs effective for enhancing the potency of an opioid agonist for asSociated with an arthritic condition or inflammation asso inhibiting progression of the arthritic condition, inflamma ciated with a chronic condition, for example, Symptoms or tion, or chronic condition, or the amount of the agonist and Signs. Such as pain, StiffneSS or difficulty in physical function. the amount of the antagonist together are effective for 0102) The present disclosure provides methods and mate inhibiting progression of the arthritic condition, inflamma rials for inhibiting progression of an arthritic condition or tion, or chronic condition. inflammation associated with chronic conditions in a human 0096. In another aspect, the amount of the antagonist is Subject including wherein the arthritic condition or inflam effective for enhancing the potency of an opioid agonist for mation associated with chronic conditions is associated with reversing damage associated with the arthritic condition, back pain by administering to the Subject an opioid antago inflammation, or chronic condition, or the amount of the nist or an opioid agonist with an opioid antagonist. For agonist and the amount of the antagonist together are example, the amount of an opioid antagonist is an amount effective for reversing damage due to the arthritic condition, effective for enhancing the potency of an opioid agonist for inflammation or chronic condition. inhibiting progression of the arthritic condition or chronic conditions associated with inflammation. The present dis 0097. In another aspect, the present disclosure provides closure thus provides methods and materials for inhibiting methods and materials for treating chronic pain by admin the change or progression in a Subject from a normal or istering to a human Subject with chronic pain an opioid uncompromised State (e.g., healthy) to an abnormal or antagonist, wherein the amount of the opioid antagonist is compromised State (e.g., diseased), as indicated, for effective for enhancing the potency of an opioid agonist to example, by a Symptom or sign associated with an arthritic attenuate the chronic pain, or the amount of the agonist and condition, inflammation from a chronic condition or chronic the amount of the antagonist together are effective to attenu pain. The progression of an arthritic condition or inflamma US 2006/0009478 A1 Jan. 12, 2006

tion associated with a chronic condition can be measured by 0107 The present methods and compositions may also be a variety of methods, including by radiography, by measur employed for the treatment of back pain from other arthritic ing levels of cytokines and/or by measuring B cell and T cell conditions, including gout and spondylarthropathris (includ Subtype ratioS. ing , Reiter's Syndrome, psoriatic 0103) The present disclosure provides methods and mate arthropathy, enterapathric spondylitis, juvenile arthropathy rials for reversing damage associated with an arthritic con or juvenile ankylosing spondylitis, and reactive arthropa dition or inflammation associated with chronic conditions in thy). The present methods and compositions may be used for a human Subject including wherein the arthritic condition or the treatment of back pain from infectious or post-infectious inflammation associated with chronic conditions is associ arthritis (including gonoccocal arthritis, tuberculous arthri ated with back pain comprising administering to the Subject tis, Viral arthritis, fungal arthritis, Syphlitic arthritis, and an opioid antagonist or an opioid agonist with an opioid Lyme disease). antagonist. For example, the amount of an opioid antagonist 0108) Additionally, the present methods and composi is an amount effective for enhancing the potency of an tions may be used for the treatment of arthritis associated opioid agonist for reversing damage due to the arthritic with various Syndromes, diseases, and conditions, Such as condition or inflammation associated with chronic condi arthritis associated with vasculitic Syndrome, arthritis asso tions. The present disclosure thus provides methods and ciated with polyarteritis nodosa, arthritis associated with materials for reversing the change or progression in a Subject hyperSensitivity vasculitis, arthritis associated with Lue from a normal or uncompromised State to an abnormal or genec's granulomatosis, arthritis associated with polymyal compromised State as indicated, for example, by a Symptom gin rheumatica, and arthritis associated with joint cell arteri or sign associated with an arthritic condition, inflammation tis. Other preferred indications contemplated for employing from a chronic condition or chronic pain. The progression of the compositions and methods herein include calcium crys the arthritic condition or inflammation associated with tal deposition arthropathies (Such as pseudo gout), non chronic conditions can be measured by a variety of methods, articular rheumatism (such as bursitis, tenosynomitis, epi including by radiography, by measuring levels of cytokines condylitis, carpal tunnel Syndrome, and repetitive use and/or by measuring B cell and T cell Subtype ratios. injuries), neuropathic joint disease, he marthrosis, Henoch 0104. The present disclosure provides compositions that Schonlein Purpura, hypertrophic osteoarthropathy, and mul comprise an opioid antagonist (e.g., an excitatory opioid ticentric reticulohistiocytosis. Other preferred indications receptor antagonist). Such compositions additionally pref contemplated for employing the compositions and methods erentially comprise an opioid agonist (e.g., a bimodally herein include arthritic conditions associated with Surcoilo acting opioid agonist), and optionally a pharmaceutically sis, hemochromatosis, Sickle cell disease and other hemo acceptable carrier or excipient for administration to a Sub globinopathries, hyperlipo proteineimia, hypogammaglobu ject, preferably a human, in need thereof. Such compositions linemia, hyperparathyroidism, acromegaly, familial optionally comprise an additional therapeutic agent. Mediterranean fever, Behat's Disease, lupus (including Sys temic lupus erythrematosis), hemophilia, and relapsing 0105. It is contemplated that the present methods and polychondritis. compositions may be employed for the treatment of inflam mation associated with chronic conditions (including inhib 0109 The methods and compositions for treating back iting progression of and/or reversing damage associated with pain, including back pain from arthritic conditions, inflam inflammation), including the chronic conditions associated mation associated with chronic conditions or chronic pain with inflammation in and around joints, muscles, bursae, alleviate (e.g., ameliorate, attenuate, reduce, diminish, tendons, Vertebrae, or fibrous tissue. Such methods and block, inhibit or prevent) at least one symptom or sign of an compositions provide reduced pain, reduced StiffneSS and/or arthritic condition, inflammation associated with a chronic improved physical function. condition, or chronic pain. For example, the methods and 0106. It is also contemplated that the present methods and compositions may alleviate one or more of pain intensity, compositions may be employed for the treatment of back stiffness, or difficulty in physical functions. The methods and pain from chronic conditions (including inhibiting progres compositions may attenuate one or more Symptoms or signs Sion of and/or reversing damage associated with chronic of an arthritic condition, inflammation associated with a conditions). Chronic conditions include, for example, chronic condition, or chronic pain, wherein the Sign or arthritic conditions Such as osteoarthritis, rheumatoid arthri Symptom after administration of the composition is amelio tis, and psoriatic arthritis. For example, the present methods rated as compared to the Sign or Symptom before adminis and compositions may be used to treat one or more Symp tration of the composition. toms or signs of osteoarthritis of the joint, (such as a hip or 0110. The present disclosure relates to compositions, knee) or the back (for example, the lower back). Chronic dosage forms, and kits with an opioid antagonist, including conditions also include, for example, conditions associated an opioid antagonist in combination with an opioid agonist, with or resulting from pain Such as chronic pain, including wherein the amount of the antagonist enhances the potency pain associated with or arising from cancer, from infection of an opioid agonist or wherein the amounts of the agonist or from the nervous system (e.g., neurogenic pain Such as and the amount of the antagonist together are effective to peripheral neurogenic pain following pressure upon or alleviate (e.g., ameliorate, attenuate, reduce, diminish, Stretching of a peripheral nerve or root or having its origin block, inhibit or prevent) one or more Symptoms or signs of in Stroke, multiple Sclerosis or trauma, including of the an arthritic condition, inflammation associated with a spinal cord). Chronic conditions also include, for example, chronic condition, or chronic pain. The disclosure further conditions associated with or arising from psychogenic pain relates to methods for administering to human Subjects Such (e.g., pain not due to past disease or injury or visible sign of compositions, dosage forms, and kits. Optionally, the damage inside or outside the nervous System). present methods and materials may further comprise admin US 2006/0009478 A1 Jan. 12, 2006 istering a pharmaceutically acceptable carrier or excipient provides a definition of improvement based on a set of for administration to the Subject, preferably a human, in measures that discriminate between active Second-line drug need thereof. Further, optimally, the present methods and treatment and placebo. These include a 20% improvement in materials may comprise an additional therapeutic agent. morning Stiffness, erythrocyte Sedimentation rate (ESR), 0111. The present disclosure also provides methods for joint tenderneSS Score, and joint Swelling Score and improve treating a Subject with pain from an arthritic condition or ment by at least 2 grades on a 5-grade scale (or from grade inflammation associated with a chronic condition, compris 2 to grade 1) for patient and physician global assessments of ing administering an amount of opioid antagonist effective current disease Severity. Current disease Severity can be to enhance the pain-alleviating potency of an opioid agonist, measured in a variety of ways, including patient or physician including an endogenous opioid agonist and optionally a global assessments, patient or physician assessments of joint pharmaceutically acceptable carrier or excipient for admin tenderness, joint Swelling Stiffness, pain, or physical func istration to the Subject, preferably a human, in need thereof, tion, cytokine levels, B-cell or T-cell Subtype ratios, eryth whereby the pain is alleviated. Such methods optionally rocyte sedimentation rate (ESR), or C-reactive protein. include additionally administering an opioid agonist, and in Suitable measures of attenuation of one or more Symptoms Such methods, the amount of antagonist is effective to or Signs, of inhibiting the progression of an arthritic condi enhance the pain-alleviating potency of the administered tion or chronic condition, or of reversing tissue or cellular agonist. damage include measuring current disease Severity. Other indexes, definitions, measures, or Scales may also be used 0112 Back pain can be associated with an arthritic con for measuring attenuation of one or more Symptoms or Signs, dition or inflammation associated with chronic conditions. inhibition of progression, or reversal of tissue or cellular The present disclosure also provides methods and materials damage. for treating back pain, including where the back pain is from an arthritic condition or inflammation associated with 0113. The present disclosure provides methods and mate chronic conditions. The methods comprise administering to rials for alleviating pain associated with arthritic conditions a human Subject an amount of an opioid antagonist or the or inflammation associated with chronic conditions. For combination of an opioid agonist and an opioid antagonist example, the amount of an opioid antagonist or the combi that is effective to enhance potency of the agonist and/or to nation of an opioid agonist and an opioid antagonist may be alleviate one or more Symptoms or signs of an arthritic effective to enhance the potency of the agonist and/or to condition or inflammation associated with a chronic condi attenuate (e.g., ameliorate, alleviate, reduce, diminish, tion, including for example, as measured by a suitable index, block, inhibit or prevent) (1) the pain felt by the Subject Scale or measure. The attenuation of one or more Symptoms when walking on a flat Surface; (2) the pain felt by the or signs of an arthritic condition or of inflammation asso Subject when going up or down Stairs; (3) the pain felt by the ciated with a chronic condition may be measured on the subject at night while in bed; (4) the pain felt by the subject WOMAC Osteoarthritis Index or one of its subscales (in that disturbs the sleep of the subject; (5) the pain felt by the other words, the pain, Stiffness, or physical function Sub Subject while sitting or lying down; and/or (6) the pain felt scales of the WOMAC Osteoarthritis Index). Any suitable by the Subject while Standing. version of the WOMAC OA Index may be used, including, 0114. Alternatively or additionally, the present disclosure for example, Version 3.0 or Version 3.1. Any suitable scale provides methods and materials for alleviating StiffneSS may be used as well. The WOMAC OA Index is available asSociated with arthritic conditions or inflammation associ in Likert and Visual Analog Scaled formats, either of which ated with chronic conditions. For example, the amount of an may be employed in the present methods. WOMAC values opioid antagonist or the combination of an opioid agonist can be considered as Surrogate markers for the diagnosis, and an opioid antagonist may be effective to enhance the prognosis, monitoring or treatment of an arthritic condition, potency of the agonist and/or to attenuate (e.g., ameliorate, inflammation from a chronic condition, and/or chronic pain. alleviate, reduce, diminish, block, inhibit or prevent) (1) the The WOMAC values represent a subjective surrogate severity of the stiffness felt by the patient after the subject marker. Alternatively or additionally, the attenuation of one first woke up in the morning; (2) the Severity of the stiffness or more Symptoms or signs may be measured on another felt by the Subject after Sitting or lying down later in the day; Suitable index, Scale or measure, Such the Australian/Cana dian (AUSCAN) Osteoarthritis Hand Index or the Osteoar and/or (3) the severity of the stiffness felt by the subject thritis Global Index (OGI). The AUSCAN 3.1 Index and while resting later in the day. User Guide are currently available from http://www.woma 0115 Alternatively or additionally, the present disclosure c.org/contact/index.cfm, as are the WOMAC 3.1 Osteoar provides methods and materials for alleviating difficulty in thritis Index and User Guide. Another Suitable measure of physical function associated with arthritic conditions or attenuation is the Definition of Improvement in Rheumatoid inflammation associated with chronic conditions. For Arthritis described in Felson et al., Arthritis & Rheumatism example, the amount of an opioid antagonist or the combi 38:727-735 (1995) incorporated herein by reference. This nation of an opioid agonist and an opioid antagonist may be measure, which also may be designated as the ACR (Ameri effective to enhance the potency of the agonist and/or to can College of Rheumatology) 20 improvement, is a com attenuate (e.g., ameliorate, alleviate, reduce, diminish, posite defined as both improvement of 20% in the number of block, inhibit or prevent) (1) the difficulty had by the subject tender and number of Swollen joints, and a 20% improve when going down stairs; (2) the difficulty had by the human ment in three of the following five: patient global, physician Subject when going up stairs; (3) the difficulty had by the global, patient pain, patient function assessment, and C-re Subject when getting up from a sitting position; (4) the active protein (CRP). Another suitable measure is described difficulty had by the subject while standing; (5) the difficulty by Paulus et al., Arthritis & Rheumatism 33:477-484 (1990) had by the subject when bending to the floor; (6) the which is incorporated herein by reference. Paulus et al. difficulty had by the patient when walking on a flat Surface; US 2006/0009478 A1 Jan. 12, 2006

(7) the difficulty had by the human subject when getting in tikine kits, available from R&D Systems, Minneapolis, or out of a car or bus; (8) the difficulty had by the subject Minn.), or several cytokines can be detected Simultaneously, while going Shopping; (9) the difficulty had by the patient using liquid or Solid based array Systems. For example, when getting out of bed; (10) the difficulty had by the subject Luminex (Austin,Tex.) has developed a liquid array System when putting on Socks, or panty hose or Stockings; (11) the based on microSpheres, wherein the Spheres contain a mix difficulty had by the subject while lying in bed; (12) the ture of two fluorophors. The ratio of the two dyes within the difficulty had by the subject when getting in or out of the mix is precisely controlled, and gives a unique spectral bathtub; (13) the difficulty had by the subject while sitting; signature to 100 different species of the microbeads. Each of (14) the difficulty had by the patient when getting on or off these 100 different species is then coated with known and the toilet; (15) the difficulty had by the subject while doing unique capture reagents, capable of interacting with mol heavy household chores; and/or (16) the difficulty had by the ecules of interest within a complex mixture Such as Serum, Subject while doing light household chores. plasma or cell culture Supernatant. These binder molecules 0116 Biomarkers have been identified, as described can be entities Such as antibodies, oligonucleotides, peptides herein, that are useful in methods and materials for the and receptors. A reporter molecule, Specific for the analyte treatment of back pain, including where the back pain is molecule of interest, is then used to quantitate binding. The from an arthritic condition, inflammation from a chronic LumineX System requires a Specific detector that uses condition and/or chronic pain, including pain from an microfluidics to detect individually labeled beads. arthritic condition or inflammation. A biomarker is a 0119) Various kits are available for use with this Luminex molecular entity, for example, a biochemical in the body, technology, including the BioSource International (Cama which has a molecular feature that makes it useful for rillo, Calif., www.biosource.com) human cytokine ten-plex diagnosis, prognosis, monitoring or treatment of a Subject, antibody bead kit. This kit measures members of two classes including, for example, measuring progress of disease or of cytokines, the TH1/TH2 and the inflammatory cytokines. effects of treatment. Biomarkers can include inflammatory The TH1/TH2 set includes IL-2, -4, -5,-10, INFY while the biomarkers. An inflammatory biomarker can be any Suitable inflammatory set is IL-1 B, IL-6, IL-8, GMOCSF, and TNF biomarker known or recognized as being related to an C. Linco (St. Charles, Mo., www.lincoresearch.com) makes inflammatory condition, including but not limited to: pro 13, 21, or 22-plex kits for cytokine measurement. The inflammatory or anti-inflammatory, Such as cytokines, inter 22-plex kit can Simultaneously measure IL-1C, IL-1B, IL-2, leukin-1 through 17, including interleukin-1C.(IL1a), inter -4, -5, -6, -7, -8, -10, -12p70, -13, -15, -17, Eotaxin, G-CSF, leukin-1 B(IL1b), IL2, IL4, IL5, IL6, IL8, IL10, IL13, tumor GM-CSF, IFNY, IP-10, MCP-1, MIP-1C, TNFoland necrosis factor alpha (TNFC), GM-CSF, interferon gamma RANTES. Another vendor, R & D Systems (Minneapolis, (IFN-Y), markers of Systemic inflammation, including, for Minn., www.rndsystems.com) makes a kit for the detection example, CRP, certain cellular adhesion molecules Such as of twelve cytokines, including INFY, bFGF, GM-CSF, e-selectin, integrins, ICAM-1, ICAM-3, BL-CAM, LFA-2, G-CSF, IL-2, -4, -5, -6, -8, -10, -17, IL-1B, IL-1C., IL-1ra, VCAM-1, NCAM, PECAM, and neopterin; and B61; leu TNFO, VEGF, ENA-78, MIP-1, MCP-1, RANTES, and kotriene, thromboxane, isoprostane, Serum amyloid A pro Tpo. Upstate (Charlottesville, Va., www.upstate.com) Sells a tein, fibrinectin, fibrinogen, leptin, prostaglandin E2, Serum variety of cytokine detection kits for use with the Luminex procalcitonin, soluble TNF receptor 2 (STNFr2), erythrocyte System that can detect up to 22 cytokines including IL-1 C, Sedimentation rate, erythema, elevated white blood count IL-1 B, IL-2, -3, -4, -5, -6, -7, -8, -10, -12(p40), -12(p70), (WBC), including percent and total granulocytes (polymor -13, -15, IP-10, Eotaxin, IFNY, GM-CSF, MCP-1, MIP-1a, phonuclear leukocytes) monocytes, lymphocytes and eosi RANTES, and TNFC. Qiagen (Valencia, Calif., www nophils; and increased erythrocyte Sedimentation rate. Fur qiagen.com) sells a kit capable of detecting 11 analytes at ther biomarkers of an inflammatory condition may include once, including Eotaxin, MCP-1, RANTES, GM-CSF, INFY, decreased levels of pre-albumin and albumin. IL-1C, IL-1B, IL-2, -4, -5, -6, -8, 10, -12p70, and IL-13. Finally, BIORAD (Hercules, Calif., www.biorad.com) sells 0117. A sample that contains or may contain a biomarker kits that can detect up to 17 cytokines at once, including: can be obtained, including a biological Sample. Biological IL-1 f, IL-2, -4, -5, -6, -7, -8, -10, -12p70, -13, -17, G-CSF, Sample refers to a sample obtained from an organism (e.g., GM-CSF, INFY, MCP-1, MIP-10, and TNFC. In addition, a human Subject) or from components (e.g., cells, tissues or there are other vendors which have similar kits available for fluids) of an organism. The sample can be a body fluid, purchase for use with the LumineX System. tissue, or cell, including, but not limited to, blood, plasma, Serum, blood cells (e.g., white cells), tissue or biopsy 0.120. Other liquid array systems are available for detec Samples (e.g., tumor biopsy), urine, Saliva, tears, Sputum, tion of cytokines such as the CBA System developed by BD Synovial fluid, cerebroSpinal fluid, peritoneal fluid, and Bioscience/Pharmingen (Franklin Lakes, N.J., www.bdbio pleural fluid, or cells therefrom. An exemplary Sample is a Sciences.com). The CBA System also uses coated beads for plasma Sample. Biological Samples can also include Sections detection of analytes. The beads are coated with binding of fluids, tissueS or cells Such as frozen Sections taken for molecules, and bound analyte is detected in a Sandwich histological purposes. assay using a phycoerytherin labeled antibody Specific for that analyte in a standard flow cytometer. BD Bioscience/ 0118 Samples can be analyzed for the presence of biom Pharmingen sells kits for detecting Several (1-7) analytes at arkers by a variety of methods. Candidate biomarkers in once and examples of these kits are the human TH1/TH2 kit Such samples can include cytokines (e.g., objective biom that measures IL-2, -4, -6, 10, TNFO and INFY, or the human arkers). Measurement of cytokines can be carried out in a inflammation kit which measures IL1B, IL6, IL8, IL10, number of ways known to those with skill in the art. TNFC and IL12p70. Bender MedSystems (Vienna, Austria, Methods are available which can detect cytokines individu www.bendermedSystems.com) has developed a product line, ally using traditional ELISA techniques (for example, Quan the Flow Cytomix system, for use with flow cytometer that US 2006/0009478 A1 Jan. 12, 2006

consists of microbeads coated with antibodies which will ines contemplated for Such use as biomarkers include IL1C, interact with various cytokines. The beads are of varying IL1 B, IL2, IL4, IL5, IL6, IL10, IL13, GM-CSF, interferon-y sizes and have unique spectral qualities due to varying and TNFC. Preferably, the cytokines TNFO, IL6, IL4, and/or amounts of an internal fluorescent dye, and these properties are used as biomarkers. allow the identification of each type of beads within a 0.124 Cytokines can be measured as biomarkers before, mixture of beads. Bender MedSystems's multicytokine kit during and/or after the administration of an opioid agonist, measures Several cytokines at once, and those to choose an opioid antagonist, or a combination of an opioid antago from include INFY, IL1B, IL-2, -4, -5, -6, -8, -12, MCP-1, nist and opioid agonist. When cytokines are to be employed TNFC. Bender also sells a TH1/TH2 kit which measures as biomarkers for a Subject, one or more cytokine levels for human IL-1B, IL-2, -4, -5, -6, -8, -10, TNFC, TNFB and that Subject are measured. Cytokines can be employed as INFY simultaneously. biomarkers, for example, for monitoring, diagnosing, prog 0121. In addition to the fluid based systems discussed nosing and/or treating the Subject, including but not limited above, methodologies are available for measuring Several to Selecting dose amounts and/or dosing regimens of an cytokines at once in Solid based array Systems. For example, opioid antagonist alone or in combination with an opioid mini array ELISA systems have been used which measure agonist. seven different cytokines, TNF-C, IFNC, IFNY, IL-1C., IL-1R, IL-6, and IL-10 (see Moody et al, BioTechniques 0125 Level(s) of one or more cytokines, for example, 31:186-194 (July 2001)). Biochips have been developed for plasma levels, can be measured in a Subject at risk for, or cytokine measurement (see Huang et al., CANCER Seeking, for example, diagnosis, prognosis, monitoring and/ RESEARCH 62, 2806-2812, May 15, 2002) wherein 43 or treatment of, or reporting, one or more signs or Symptoms cytokines can be detected including GM-CSF, G-CSF, of back pain from an arthritic condition or inflammation IL-1C, IL-1B, IL-2, -3, -4, -5, 6, -8, -10, -12, -13, TNFC. and asSociated with a chronic condition, and/or chronic back VEGF. Array systems on glass slides have been developed pain, including chronic back pain from an arthritic condition (Tam et al. Journal of Immunological Methods 261: 157-165 or inflammation. For example, depending on the measured (2002)), for example, capable of measuring eight cytokines cytokine level(s), an appropriate treatment can be selected and administered. The measured cytokine level(s) can be including INFY, IL-2, -4, -5,-6, -10 and -13 and TNFC), or used to determine whether and how much opioid agonist rolling circle amplified-antibody arrays which can measure and/or opioid antagonist are administered. Furthermore, for up to 75 cytokines simultaneously (Schweitzer et al, Nature example, the dose amount and/or dosing regimen of an Biotechnology 20:359-365 (2002)) including IL-1C, IL-1R, opioid agonist, an opioid antagonist, or a combination of an IL-2, -4, -5, -6, -8, 10, -12, TNFO, RANTES and VEGF. opioid antagonist and opioid agonist can be selected based 0122). Other array Systems, capable of acting either as upon the measured cytokine level(s). For example, if one or fluid- or solid-based systems, are available from Pointilliste more of the measured cytokine levels is above a value, a (Mountain View, Calif., http://www.pointilliste.com). This physician can choose to treat a Subject by administering an flexible technology is comprised of Self assembling arrays in opioid agonist, an opioid antagonist, or a combination of which the user is able to Specifically Select the analytes they opioid antagonist and opioid agonist. The value can be a wish to Study. A reporter molecule, Specific for the analyte predetermined value or a value determined at the time of or molecule of interest, is then used to quantitate binding. AS after measurement of the cytokine level(s). As another used herein, the measurements are done on a Solid Support example, a physician can Select a higher or lower amount of where capture antibody arrays are applied to a canvas, opioid agonist and/or a higher or lower amount of antagonist wherein each canvas contains up to 96 arrays, and each array for administration. As yet another example, a more frequent may contain up to 625 addressable spots. In this way, each or less frequent dosing regimen can be selected based on the canvas may contain up to 14 million unique, addressable measured cytokine level(s). For example, if the level of molecules. Anti-cytokine arrayS can be prepared in this cytokines are higher than desired, an opioid antagonist can System, making use of paired antibodies Sets Such as for be dosed more frequently, or if the level of cytokines are example, Cytosets, available from BioSource International. lower than desired, an opioid antagonist can be dosed leSS A commercial human Th1/Th2 cytokine canvas is available frequently. from Pointilliste and was used as described in Example 4. 0126 Level(s) of one or more cytokines, for example, 0123. One or more cytokines can be employed as biom plasma levels, can be measured for a Subject who has arkers for treatment using methods and materials as already received or who is receiving treatment for back pain described herein. For example, one or more cytokines can be from an arthritic condition or inflammation associated with employed as a biomarker for treatment of an arthritic a chronic condition, and/or chronic back pain, including condition, inflammation associated with a chronic condition, chronic back pain from an arthritic condition or inflamma and/or chronic pain, including pain from an arthritic condi tion. The measured cytokine level(s) can be used to deter tion or inflammation. One or more cytokines can be used as mine whether appropriate amounts and regimens have been a biomarker of the existence or extent (e.g., diagnosis, or are being employed for treating the Subject. For example, prognosis, monitoring) of an arthritic condition, of inflam level(s) of one or more cytokines can be measured in a mation associated with a chronic condition, and/or of Subject receiving treatment for back pain from an arthritic chronic pain, including pain from arthritic conditions or condition or inflammation associated with a chronic condi inflammation. Alternatively or additionally, one or more tion, and/or chronic back pain, including chronic back pain cytokines can be used as a biomarker to assess the treatment from an arthritic condition or inflammation. If the one or of an arthritic condition, inflammation associated with a more of the measured cytokine levels is above a value, the chronic condition, and/or chronic pain, including pain from treatment can be adjusted by administering a greater or an arthritic condition or inflammation. Examples of cytok lesser amount of an opioid agonist, an opioid antagonist, or US 2006/0009478 A1 Jan. 12, 2006 a combination of opioid antagonist and opioid agonist and/or combined use of an opioid antagonist with an opioid agonist by altering the dosing regimen. The value can be a prede can be selected for Seeking a desired effect. The plasma termined value or a value determined at the time of or after concentration-effect relationship of low dose of an opioid measurement of the cytokine level(s). antagonist when administered with an opioid agonist has 0127 Concentrations of cytokines, for example, plasma been represented for the first time by the Emax composite concentrations, can be used as biomarkers in adjusting the model: administration of an opioid antagonist to a Subject. A Single cytokine concentration can be Selected to evaluate whether EC522+Cp'n' a Subject is in need of treatment. AS an example, if a Subject where the respective Emax values represent maximum effect has a plasma concentration of TNFC. which is higher than for a given drug, EC51 and EC52 represent the potencies, about 0.08 ng/ml, alternatively higher than 0.2 ng/ml, the for the drug notated as either 1 or 2, respectively (in other Subject is administered more opioid antagonist and/or more words, EC51 is not the concentration having 51% of the opioid agonist, by administering higher dose amounts and/or maximal effect, but rather EC51 is the concentration having by administering on a more frequent dosing regimen. AS a particular potency (e.g. 50% of the maximal effect for another example, if the Subject has a plasma concentration Effect No. 1); the respective values for C are the concen of TNFC. which is about 0.08 ng/ml or lower, alternatively trations of drugs notated as 1 or 2, and the values of n, and lower than 0.2 ng/ml, either the administration of opioid in that correspond to the Sigmoidicity factors that are asso antagonist is not changed, or the Subject is administered leSS ciated with particular EC values. In the Emax composite opioid antagonist and/or less opioid agonist, by administer model, "+" is used to indicate absolute values, Sometimes it ing lower dose amounts and/or by administering on a leSS is shown as a "- which reflects a negative Second term. frequent dosing regimen. AS another example, if a Subject 0.130. The Emax composite model is a recognized com has a plasma concentration of ILA which is higher than about posite model for PK/PD data analysis set forth, for example, 0.23 ng/ml, the Subject is administered more opioid antago in Gabrielsson et al., PHARMACOKINETIC/PHARMA nist and/or more opioid agonist, by administering higher CODYNAMIC DATA ANALYSIS: CONCEPTS AND dose amounts and/or by administering on a more frequent APPLICATIONS, pp. 191-193 and 801-808 (2000), and the dosing regimen. AS another example, if the Subject has a computer command files provided with the reference and plasma concentration of IL4 which is about 0.23 ng/ml or described, including with examples of the computer print lower, either the administration of opioid antagonist is not outs on pages 801-808, all of which is incorporated by changed, or the Subject is administered leSS opioid antago reference herein. However, it is believed that the Emax nist and/or less opioid agonist, by administering lower dose composite model has not previously been utilized for the amounts and/or by administering on a less frequent dosing analysis of PK data from administering low doses of opioid regimen. AS another example, if a Subject has a plasma antagonists Such as naltrexone for enhancing the potency of concentration of IL6 which is higher than about 0.18 ng/ml, opioid agonists Such as Oxycodone, as described herein. the Subject is administered more opioid antagonist and/or From the plasma concentration-effect data obtained and more opioid agonist, by administering higher dose amounts described in Example 3, it is contemplated that the opioid and/or by administering on a more frequent dosing regimen. antagonist, at lower plasma concentrations, is impacting the AS another example, if the Subject has a plasma concentra total effect (percent change in pain intensity), primarily as tion of IL6 which is about 0.18 ng/ml or lower, either the described by the terms of the equation denoted with a 2. administration of opioid antagonist is not changed, or the Subject is administered less opioid antagonist and/or leSS 0131 The recognition of the applicability and utility of a opioid agonist, by administering lower dose amounts and/or composite model as shown above enables the Selection of by administering on a leSS frequent dosing regimen. preferred and/or Suitable ranges for the combined use of an opioid antagonist with an opioid agonist as described herein. 0128. One or more cytokine concentrations can be used The composite model provides the relative contribution of as biomarkers in adjusting the administration of an opioid an opioid antagonist with respect to enhancing pain relief, antagonist to a Subject. For example, one or more of the for example, as measured by a reduction in pain intensity. concentrations of IL1C., IL1B, IL2, IL4, IL5, IL6, IL10, The effective percentage decrease in pain intensity, E, has IL13, GM-CSF, interferon-Y and TNFC. can be used to been found to be described by a relatively wide scope of determine or adjust the treatment of back pain from an preferred plasma concentrations by the Emax composite arthritic condition or inflammation associated with a chronic model, as described in Example 3 and as shown in the data condition, and/or chronic back pain, including chronic back and Figures described herein. pain from an arthritic condition or inflammation. 0132) Opioids refer to compounds or compositions, 0129 Concentrations of agonist, antagonists, Surrogates including metabolites of the compounds or compositions, Such as 6f-naltrexol and/or biomarkerS Such as cytokines that bind to specific opioid receptorS and have agonist can be useful in methods and materials for the treatment of (activation) or antagonist (inactivation) effects at the opioid back pain, including where the back pain is from an arthritic receptors. condition, inflammation from a chronic condition and/or chronic pain, including pain from an arthritic condition or 0.133 Inhibitory opioid receptors refer to opioid receptors inflammation. Such concentrations are particularly useful that mediate inhibitory opioid receptor functions, Such as where a relationship is known between the concentration analgesia. and an effect on the Subject. For example, where the rela 0134) Opioid receptor agonist or opioid agonist refers to tionship between the effect of an opioid antagonist and a an opioid compound or composition, including any active concentration of an agonist, antagonist Surrogate or a biom metabolite of Such compound or composition, that binds to arker is known, preferred and/or Suitable ranges for the and activates opioid receptors on neurons that mediate pain. US 2006/0009478 A1 Jan. 12, 2006

0.135 An opioid receptor antagonist or opioid antagonist amount from at least about 0.000001 mg to about or less than refers to an opioid compound or composition, including any about 0.5 or 1.0 mg, 0.00001 mg to about or less than about active metabolite of Such compound or composition, for 0.5 or 1.0 mg, 0.0001 mg to about or less than about 0.5 or example, that binds to and blockS opioid receptors on 1.0 mg, or at least about 0.001 mg to about or less than about neurons that mediate pain. An opioid antagonist attenuates 0.5 or 1.0 mg, or at least about 0.01 mg to about or less than (e.g., blocks, inhibits, prevents, or competes with) the action about 0.5 or 1.0 mg, or at least about 0.1 mg to about or less of an opioid agonist. than about 0.5 or 1.0 mg. Preferred ranges of opioid antago nists also include: from about 0.000001 mg to less than 0.2 0.136 Pharmaceutically acceptable refers to those com mg; from about 0.00001 mg to less than 0.2 mg; from about pounds, materials, compositions, and/or dosage forms which 0.0001 mg to less than 0.2 mg; from about 0.001 mg to less are, within the Scope of Sound medical judgment, Suitable than 0.2 mg; from about 0.01 mg to less than 0.2 mg; or from for use in contact with the tissueS of human beings and about 0.1 mg to less than 0.2 mg. Additional preferred animals without excessive toxicity, irritation, allergic ranges of opioid antagonists include: from about 0.0001 mg response, or other problems or complications, commensu to about 0.1 mg; from about 0.001 mg to about 0.1 mg; from rate with a reasonable benefit/risk ratio. about 0.01 mg to about 0.1 mg; from about 0.001 mg to 0.137 Pharmaceutically acceptable salts refer to deriva about 0.1 mg; from about 0.001 mg to about 0.01 mg; or tives of the disclosed compounds wherein the compounds from about 0.01 mg to about 0.1 mg. are modified by making at least one acid or base Salt thereof, 0144. In a preferred dosage form, the maximum amount and includes inorganic and organic Salts. of antagonist is 1 mg, alternatively less than 1 mg, alterna tively 0.99 mg, alternatively 0.98 mg, alternatively 0.97 mg, 0.138 An analgesic amount of opioid agonist refers to an alternatively 0.96 mg, alternatively 0.95 mg, alternatively amount of the opioid agonist which causes analgesia in a 0.94 mg, alternatively 0.93 mg, alternatively 0.92 mg, patient administered the opioid receptor agonist alone, and alternatively 0.91 mg, alternatively 0.90 mg, alternatively includes Standard doses of the agonist which are typically 0.89 mg, alternatively 0.88 mg, alternatively 0.87 mg, administered to cause analgesia (e.g. mg doses). alternatively 0.86 mg, alternatively 0.85 mg, alternatively 0.139. A subanalgesic amount of opioid agonist refers to 0.84 mg, alternatively 0.83 mg, alternatively 0.82 mg, an amount which does not cause analgesia in a patient alternatively 0.81 mg, alternatively 0.80 mg, alternatively administered the opioid receptor agonist alone, but when 0.79 mg, alternatively 0.78 mg, alternatively 0.77 mg, used in combination with a potentiating or enhancing alternatively 0.76 mg, alternatively 0.75 mg, alternatively amount of opioid antagonist, results in analgesia. 0.74 mg, alternatively 0.73 mg, alternatively 0.72 mg, alternatively 0.71 mg, alternatively 0.70 mg, alternatively 0140. An effective antagonistic amount of opioid agonist 0.69 mg, alternatively 0.68 mg, alternatively 0.67 mg, refers to an amount that effectively attenuates (e.g. amelio alternatively 0.66 mg, alternatively 0.65 mg, alternatively rates, reduces, diminishes, blocks, inhibits, prevents, or 0.64 mg, alternatively 0.63 mg, alternatively 0.62 mg, competes with) the analgesic activity of an opioid agonist. alternatively 0.61 mg, alternatively 0.60 mg, alternatively 0.141. A therapeutically effective amount of a composi 0.59 mg, alternatively 0.58 mg, alternatively 0.57 mg, tion refers to an amount that elicits alleviation (e.g., ame alternatively 0.56 mg, alternatively 0.55 mg, alternatively lioration, attenuation, reduction, diminishment, blockage, 0.54 mg, alternatively 0.53 mg, alternatively 0.52 mg, inhibition or prevention) of at least one sign or Symptom of alternatively 0.51 mg, alternatively 0.50 mg. an arthritic condition, inflammation associated with a 0145 Additionally, the maximum amount of antagonist chronic condition, or chronic pain upon administration to a in the dosage form is less than 0.5 mg, alternatively 0.49 mg, patient in need thereof. alternatively 0.48 mg, alternatively 0.47 mg, alternatively 0.46 mg, alternatively 0.45 mg, alternatively 0.44 mg, 0142. The antagonist in the present compositions may be alternatively 0.43 mg, alternatively 0.42 mg, alternatively present in its original form or in the form of a pharmaceu 0.41 mg, alternatively 0.40 mg, alternatively 0.39 mg, tically acceptable Salt. The antagonists in the present com alternatively 0.38 mg, alternatively 0.37 mg, alternatively positions include: naltrexone, naloxone, nalmefene, meth 0.36 mg, alternatively 0.35 mg, alternatively 0.34 mg, ylnaltrexone, methiodide, nalorphine, naloxonazine, nalide, alternatively 0.33 mg, alternatively 0.32 mg, alternatively nalmexone, nalorphine dinicotinate, naltrindole (NTI), nal 0.31 mg, alternatively 0.30 mg, alternatively 0.29 mg, trindole isothiocyanate, (NTII), naltriben (NTB), nor-binal alternatively 0.28 mg, alternatively 0.27 mg, alternatively torphimine (nor-BNI), b-funaltrexamine (b-FNA), BNTX, 0.26 mg, alternatively 0.25 mg, alternatively 0.24 mg, cyprodime, ICI-174,864, LY117413, MR2266, or an opioid alternatively 0.23 mg, alternatively 0.22 mg, alternatively antagonist having the same pentacyclic nucleus as 0.21 mg, alternatively 0.20 mg, alternatively 0.19 mg, nalmefene, naltrexone, levorphanol, meptazinol, dezocine, alternatively 0.18 mg, alternatively 0.17 mg, alternatively or their pharmacologically effective esters or Salts. Preferred 0.16 mg, alternatively 0.15 mg, alternatively 0.14 mg, opioid antagonists include naltrexone, nalmefene, naloxone, alternatively 0.13 mg, alternatively 0.12 mg, alternatively or mixtures thereof. Particularly preferred is nalmefene or 0.11 mg, alternatively 0.10 mg, alternatively 0.09 mg, alter naltrexone. natively 0.08 mg, alternatively 0.07 mg, alternatively 0.06 0143. In general, for compositions, dosage forms, kits mg, alternatively 0.05 mg, alternatively 0.04 mg, alterna and methods according to the present disclosure, an opioid tively 0.03 mg, alternatively 0.02 mg, alternatively 0.01 mg, antagonist is provided in an amount from about 1 fg to about alternatively 0.009 mg, alternatively 0.008 mg, alternatively 1.0 mg or from about 1 fg to about 1 lug including where the 0.007 mg, alternatively 0.006 mg, alternatively 0.005 mg, amount is provided by administration 1, 2, 3, or 4 times per alternatively 0.004 mg, alternatively 0.003 mg, alternatively day. Alternatively, the opioid antagonist is provided in an 0.002 mg, alternatively 0.001 mg, alternatively 0.0009 mg, US 2006/0009478 A1 Jan. 12, 2006 alternatively 0.0008 mg, alternatively 0.0007 mg, alterna 0.51 mg, alternatively 0.52 mg, alternatively 0.53 mg, tively 0.0006 mg, alternatively 0.0005 mg, alternatively alternatively 0.54 mg, alternatively 0.55 mg, alternatively 0.0004 mg, alternatively 0.0003 mg, alternatively 0.0002 0.56 mg, alternatively 0.57 mg, alternatively 0.58 mg, mg. alternatively 0.59 mg, alternatively 0.6 mg, alternatively 0.61 mg, alternatively 0.62 mg, alternatively 0.63 mg, 0146 The minimum amount of antagonist in the dosage alternatively 0.64 mg, alternatively 0.65 mg, alternatively form is 0.0001 mg, alternatively 0.0002 mg, alternatively 0.66 mg, alternatively 0.67 mg, alternatively 0.68 mg, 0.0003 mg, alternatively 0.0004 mg, alternatively 0.0005 alternatively 0.69 mg, alternatively 0.7 mg, alternatively mg, 0.0006 mg, alternatively 0.0007 mg, alternatively 0.0008 mg, alternatively 0.0009 mg, alternatively 0.001 mg, 0.71 mg, alternatively 0.72 mg, alternatively 0.73 mg, alternatively 0.002 mg, alternatively 0.003 mg, alternatively alternatively 0.74 mg, alternatively 0.75 mg, alternatively 0.004 mg, alternatively 0.005 mg, alternatively 0.006 mg, 0.76 mg, alternatively 0.77 mg, alternatively 0.78 mg, alternatively 0.007 mg, alternatively 0.008 mg, alternatively alternatively 0.79 mg, alternatively 0.8 mg, alternatively 0.009 mg, alternatively 0.01 mg, alternatively 0.011 mg, 0.81 mg, alternatively 0.82 mg, alternatively 0.83 mg, alternatively 0.012 mg, alternatively 0.013 mg, alternatively alternatively 0.84 mg, alternatively 0.85 mg, alternatively 0.014 mg, alternatively 0.015 mg, alternatively 0.016 mg, 0.86 mg, alternatively 0.87 mg, alternatively 0.88 mg, alternatively 0.017 mg, alternatively 0.018 mg, alternatively alternatively 0.89 mg, alternatively 0.9 mg, alternatively 0.019 mg, alternatively 0.02 mg, alternatively 0.021 mg, 0.91 mg, alternatively 0.92 mg, alternatively 0.93 mg, alternatively 0.022 mg, alternatively 0.023 mg, alternatively alternatively 0.94 mg, alternatively 0.95 mg, alternatively 0.024 mg, alternatively 0.025 mg, alternatively 0.026 mg, 0.96 mg, alternatively 0.97 mg, alternatively 0.98 mg, alternatively 0.027 mg, alternatively 0.028 mg, alternatively alternatively 0.99 mg. 0.029 mg, alternatively 0.03 mg, alternatively 0.031 mg, 0147 In a more preferred dosage form, the maximum alternatively 0.032 mg, alternatively 0.033 mg, alternatively amount of antagonist is less than 0.0020 mg, alternatively 0.034 mg, alternatively 0.035 mg, alternatively 0.036 mg, 0.0019 mg, alternatively 0.0018 mg, alternatively 0.0017 alternatively 0.037 mg, alternatively 0.038 mg, alternatively mg, alternatively 0.001.6 mg, alternatively 0.0015 mg, alter 0.039 mg, alternatively 0.04 mg, alternatively 0.04.1 mg, natively 0.0014 mg, alternatively 0.0013 mg, alternatively alternatively 0.042 mg, alternatively 0.043 mg, alternatively 0.0012 mg, alternatively 0.0011 mg, alternatively 0.0010 0.044 mg, alternatively 0.045 mg, alternatively 0.046 mg, mg, alternatively 0.0009 mg, alternatively 0.0008 mg, alter alternatively 0.047 mg, alternatively 0.048 mg, alternatively natively 0.0007 mg, alternatively 0.0006 mg, alternatively 0.049 mg, alternatively 0.05 mg, alternatively 0.051 mg, 0.0005 mg, alternatively 0.0004 mg, alternatively 0.0003 alternatively 0.052 mg, alternatively 0.053 mg, alternatively mg, alternatively 0.0002 mg, alternatively 0.0001 mg. 0.054 mg, alternatively 0.055 mg, alternatively 0.056 mg, alternatively 0.057 mg, alternatively 0.058 mg, alternatively 0.148. In a more preferred dosage form, the minimum 0.059 mg, alternatively 0.06 mg, alternatively 0.061 mg, amount of antagonist in the preferred dosage form is 0.0001 alternatively 0.062 mg, alternatively 0.063 mg, alternatively mg, alternatively 0.0002 mg, alternatively 0.0003 mg, alter 0.064 mg, alternatively 0.065 mg, alternatively 0.066 mg, natively 0.0004 mg, alternatively 0.0005 mg, alternatively alternatively 0.067 mg, alternatively 0.068 mg, alternatively 0.0006 mg, alternatively 0.0007 mg, alternatively 0.0008 0.069 mg, alternatively 0.07 mg, alternatively 0.071 mg, mg, alternatively 0.0009 mg, alternatively 0.0010 mg, alter alternatively 0.072 mg, alternatively 0.073 mg, alternatively natively 0.0011 mg, alternatively 0.0012 mg, alternatively 0.074 mg, alternatively 0.075 mg, alternatively 0.076 mg, 0.0013 mg, alternatively 0.0014 mg, alternatively 0.0015 alternatively 0.077 mg, alternatively 0.078 mg, alternatively mg, alternatively 0.001.6 mg, alternatively 0.0017 mg, alter 0.079 mg, alternatively 0.08 mg, alternatively 0.081 mg, natively 0.0018 mg, alternatively 0.0019 mg, alternatively alternatively 0.082 mg, alternatively 0.083 mg, alternatively 0.002 mg. 0.084 mg, alternatively 0.085 mg, alternatively 0.086 mg, 0149 Any minimum amount and any maximum amount alternatively 0.087 mg, alternatively 0.088 mg, alternatively of antagonist in the dosage form, as Specified above, may be 0.089 mg, alternatively 0.09 mg, alternatively 0.091 mg, alternatively 0.092 mg, alternatively 0.093 mg, alternatively combined to define a range of amounts, providing that the 0.094 mg, alternatively 0.095 mg, alternatively 0.096 mg, minimum Selected is equal to or less than the maximum alternatively 0.097 mg, alternatively 0.098 mg, alternatively Selected. 0.099 mg, alternatively 0.1 mg, alternatively 0.11 mg, alter 0150. The amount of an opioid antagonist in the compo natively 0.12 mg, alternatively 0.13 mg, alternatively 0.14 Sitions for use in methods according to the present disclosure mg, 0.15 mg, alternatively 0.16 mg, alternatively 0.17 mg, effective to enhance the potency of an opioid agonist can be alternatively 0.18 mg, alternatively 0.19 mg, alternatively less than an effective antagonistic amount. The effective 0.2 mg, alternatively 0.21 mg, alternatively 0.22 mg, alter amount of an opioid antagonist in the present compositions natively 0.23 mg, alternatively 0.24 mg, alternatively 0.25 can be about 0.002 mg. The effective amount of an opioid mg, alternatively 0.26 mg, alternatively 0.27 mg, alterna antagonist in the present compositions can be less than 0.002 tively 0.28 mg, alternatively 0.29 mg, alternatively 0.3 mg, mg. The effective amount of an opioid antagonist in the alternatively 0.31 mg, alternatively 0.32 mg, alternatively present compositions can be about 0.001 mg. The effective 0.33 mg, alternatively 0.34 mg, alternatively 0.35 mg, amount of an opioid antagonist in the present compositions alternatively 0.36 mg, alternatively 0.37 mg, alternatively can be less than 0.001 mg. The effective amount of an opioid 0.38 mg, alternatively 0.39 mg alternatively 0.40 mg, alter antagonist in the present compositions can be more than natively 0.41 mg, alternatively 0.42 mg, alternatively 0.43 0.0001 mg. The effective amount of an opioid antagonist in mg, alternatively 0.44 mg, alternatively 0.45 mg, alterna the present compositions can be about 0.0001 mg. The tively 0.46 mg, alternatively 0.47 mg, alternatively 0.48 mg, effective amount of an opioid antagonist in the present alternatively 0.49 mg, alternatively 0.5 mg, alternatively compositions can be about 0.00001 mg. The effective US 2006/0009478 A1 Jan. 12, 2006

amount of an opioid antagonist in the present compositions may be, for example, 5%, 50% or 90%, or some other can be less than 0.00001 mg. The effective amount of an percentage between 1% and 100%. The desired time may be opioid antagonist in the present compositions can be more in minutes or hours, for example, 10 minutes, 20 minutes, 30 than 0.00001 mg. The effective amount of an opioid antago minutes, or 45 minutes, or Some other time. The desired nist in the present compositions can be about 0.000001 mg. portion and the desired time may be varied by the inclusion The effective amount of an opioid antagonist in the present of formulants for the controlled release or Sustained release compositions can be less than 0.000001 mg. The effective of any therapeutic agent(s). amount of an opioid antagonist in the present compositions 0154) The optimum amounts of the opioid antagonist can be more than 0.000001 mg. administered in combination with an opioid agonist or other 0151. Any of the foregoing effective amounts may be therapeutic agent will of course depend upon the particular administered one time per day, alternatively two times per antagonist and agonist or other agent used, the excipient day, alternatively three times per day, alternatively four chosen, the route of administration, and/or the pharmacoki times per day, preferably two times per day. Alternatively netic properties of the patient being treated. Effective admin any of the following effective amounts may be divided over istration levels of antagonist and agonist or other agent will a Series of dosages within one day or other relevant time vary upon the State and circumstances of the patient being period. For example, the effective amount may be divided treated. AS those skilled in the art will recognize, many into one, two, three or four doses administered over the day factors that modify the action of an active ingredient will be or other time period. Preferred effective amounts of an taken into account by a treating physician, Such as the age, opioid antagonist include a total daily dose from about body weight, Sex, diet, and condition of the patient, the lapse 0.00002 mg to about 0.002 mg, wherein the total daily dose of time between the condition or injury and the administra is divided into 1, 2, 3, or 4 doses. For example, where the tion of the present compositions, and the administration dose is administered two times per day, the opioid antagonist technique. A person of ordinary skill in the art will be able in preferably in an amount from about 0.00001 mg to about to ascertain the optimal dosage for a given Set of conditions 0.001 mg in each of the two doses. Alternatively, where the in view of the disclosure herein. dose is administered one time per day, the opioid antagonist O155 The opioid agonist and/or antagonist can be present in an amount from about 0.00002 mg to about 0.002 mg in in the present compositions as an acid, base, pharmaceuti the dose. Alternatively, where the dose is administered four cally acceptable Salt, or a combination thereof. The phar times per day, the opioid antagonist in an amount from about maceutically acceptable Salt embraces inorganic or organic 0.000005 mg to about 0.0005 mg in each of the four doses. salts. Examples of pharmaceutically acceptable salts 0152 The amount of antagonist in a dosage form may be include, but are not limited to, mineral or organic acid Salts. less than an effective amount to antagonize an exogenous or The pharmaceutically acceptable Salts include the conven endogenous agonist, but Such an amount is effective to tional non-toxic Salts made, for example, from non-toxic enhance the pain-enhancing potency, including the inflam inorganic or organic acids. For example, Such conventional matory pain-enhancing potency, of the agonist and option non-toxic Salts include those derived from inorganic acids ally but preferably is effective to attenuate an adverse effect Such as hydrochloric, hydrobromic, Sulfuric, Sulfonic, Sul of the agonist, for example, tolerance, withdrawal, depen famic, phosphoric, nitric and others known to those skilled dence and/or addiction. Alternatively, the opioid agonist can in the art; and the Salts prepared from organic acids Such as be administered, in either a combined dosage form with the amino acids, acetic, propionic, Succinic, glycolic, Stearic, antagonist or in a separate dosage form. The present disclo lactic, malic, malonic, tartaric, citric, ascorbic, pamoic, Sure also provides an immediate release Solid oral dosage maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, form comprising one or more pharmaceutical excipients, a Salicylic, Sulfanilic, 2-acetoxybenzoic, fumaric, toluene dose of an opioid agonist and a low dose of an opioid Sulfonic, methaneSulfonic, ethane disulfonic, oxalic, antagonist, wherein the opioid agonist and opioid antagonist isethionic, glucuronic, and other acids. Other pharmaceuti cally acceptable Salts and variants include mucates, phos are release concurrently when placed in an aqueous envi phate (dibasic), phosphate (monobasic), acetate trihydrate, ronment. The opioid antagonist and opioid agonist can be bi(heptafluorobutyrate), bi(methylcarbamate), bi(pentafluo formulated as immediate release, (IR), controlled release ropropionate), meSylate, bi(pyridine-3-carboxylate), bictrif (CR) and/or sustained released (SR) formulations. Formu luoroacetate), bitartrate, chlorhydrate, and Sulfate pentahy lations can have components that are combinations of IR drate. An oxide, though not usually referred to by chemists and/or CR and/or SR components. as a Salt, is also a “pharmaceutically acceptable Salt for the 0153. The combination dosage forms of the present com present purpose. For acidic compounds, the Salt may include positions can be formulated to provide a concurrent release an amine-based (primary, Secondary, tertiary or quaternary of the opioid antagonist in combination with opioid agonist amine) counterion, an alkali metal cation, or a metal cation. and/or other therapeutic agent generally throughout at least Lists of Suitable Salts are found in texts. Such as Remington's a majority of the delivery profile for the formulation. As Pharmaceutical Sciences, 18" Ed. (Alfonso R. Gennaro, used herein, the terms “concurrent release' and “released ed., Mack Publishing Company, Easton, Pa., 1990); Rem concurrently mean that the agonist and antagonist are ington: the Science and Practice of Pharmacy 19" Ed. (Lip released in in vitro dissolution assays in an overlapping pincott, Williams & Wilkins, 1995); Handbook of Pharma manner. The respective beginnings of release of each agent ceutical Excipients, 3" Ed. (Arthur H. Kibbe, ed.; Amer. can but need not necessarily be simultaneous. Concurrent Pharmaceutical Assoc., 1999); the Pharmaceutical Codex: release will occur when the majority of the release of the first Principles and Practice of Pharmaceutics 12" Ed. (Walter agent overlap a majority of release of the Second agent. A Lund ed., Pharmaceutical Press, London, 1994); The United desired portion of each active pharmaceutical ingredient States Pharmacopeia: The National Formulary (United may be released within a desired time. The desired portions States Pharmacopeial Convention); and Goodman and Gil US 2006/0009478 A1 Jan. 12, 2006 man's: the Pharmacological Basis of Therapeutics (Louis S. 0160 In an embodiment, the present compositions may Goodman and Lee E. Limbird, eds.; McGraw Hill, 1992), further comprise, at least one mscle relaxant. Representative the disclosures of which are all incorporated herein by muscle relaxants include acetylcholine inhibitorS Such as reference. Additional representative Salts include hydrobro Botox, neuromuscular blocking agents Such as rocuronium mide, hydrochloride, mucate, Succinate, n-Oxide, Sulfate, (ZEMURONGR), succinylcholine (ANECTINE, others), malonate, acetate, phosphate dibasic, phosphate monobasic, d-tubocurarine, atracurium (TRACRIUM), doxacurium acetate trihydrate, bi(heplafluorobutyrate), maleate, bi(m- (NUROMAX), mivacurium (MIVACRON), pancuronium ethylcarbamate), bi(pentafluoropropionate), meSylate, (PAVULON), pipecuronium (ARDUAN), rapacuronium bi(pyridine-3-carboxylate), bi(trifluoroacetate), bit artrate, (RAPLON), and vecuronium (NORCURON), and skeletal chlorhydrate, fumarate, and Sulfate pentahydrate. muscle relaxants & combinatives Such as dantrolene (Dant 0156 The methods may further comprise administering rium), cyclobenzaprine (Flexeril(R), orphenadrine (Nor to the Subject another therapeutic agent, for example, non flex(R), carisoprodol (Soma(R), and diazepam (Valium(R). Steroidal anti-inflammatory drug agents or local anesthetic 0.161 With regard to dosage levels, the non-narcotic and/or analgesic agents, muscle relaxants, antidiarrheal analgesic is present in a inflammatory pain-alleviating agents Such as loperamide, TNF-C. antagonists, corticoster amount or an amount that is not pain-alleviating alone but is oids, disease-modifying anti-rheumatic drugs (DMARDs), pain-alleviating in combination with an opioid agonist and anticonvulsant agents, tricyclic antidepressant agents, anti opioid antagonist according to the present disclosure. This dynorphin agents, glutamate receptor antagonist agents. In amount is at a level corresponding to the generally recom particularly, it is Specifically completed that, in addition to mended adult human dosages for a particular non-narcotic the opioid agonist and the opioid antagonist, the Subject may analgesic. The effective inflammatory pain-alleviating be administered TNF-C. antagonists, P38 inhibitors, and amount of the opioid antagonist and the opioid agonist can cytokines inhibitors (including but not limited to IL-2, IL-6, be present at a level that potentiates the inflammatory IL-8, and GM-CSF). The opioid agonist, the opioid antago pain-alleviating effectiveness of the non-narcotic analgesic. nist, and other therapeutic agent may be administered to the Specific dosage levels for the non-narcotic analgesic that can Subject in a combined dosage form. be used herein as given, inter alia, in the “Physicians Desk O157 An NSAID refers to a non-steroidal anti-inflam Reference”, 2003 Edition (Medical Economics Data Pro matory drug and includes anti-inflammatory drugs. Such as duction Company, Montvale, N.J.) as well as in other aspirin, members of the cycloxgenease I, II and III inhibi reference works including Goodman and Gilman’s “The tors, and includes naproxen Sodium, diclofenac and miso Pharmaceutical Basis of Therapeutics” and “Remington's prostol, Valdecoxib, diclofenac, celecoxib, Sulindac, Pharmaceutical Sciences,” the disclosures of all are incor Oxaprozin, diflunisal, piroXicam, indomethacin, meloxicam, porated herein by reference. AS is well known to one of ibuprofen, naproxen, mefenamic acid, nabumetone, ketoro ordinary skill in the art, there can be a wide variation in the lac, choline or magnesium Salicylates, rofecoxib, tolmetin dosage level of the non-narcotic analgesic, wherein the Sodium, phenylbutaZone, oxyphenbutZone, meclofenamate dosage level depends to a large extent on the Specific Sodium or difluSenal. non-narcotic analgesic being administered. These amounts can be determined for a particular drug combination in 0158. In an embodiment, the present compositions fur accordance with the present disclosure by employing routine ther comprise at least one non-narcotic analgesic, Such as a experimental testing. nonsteroidal anti-inflammatory agent (NSAID). Represen tative nonsteroidal anti-inflammatory agents include aspirin, 0162. In an embodiment, the present compositions fur diclofenac, difluSinal, etodolac, fenbufen, fenoprofen, ther comprise at least one inhibitor of TNF-C. Inhibitors of flufenisal, flurbiprofen, ibuprofen, indomethacin, ketopro TNF-C. may also be designated TNF-C. antagonists. TNF-C. fen, ketorolac, meclofenamic acid, mefenamic acid, nabu antagonists are compounds which are capable of, directly or metone, naproxen, Oxaprozin, phenylbutaZone, piroXican, indirectly, counteracting, reducing or inhibiting the biologi Sulindac, tolmetin, and Zomepirac. Currently marketed cal activity of TNF-C., or the activation of receptors there NSAIDs include Celebrex(R), Vioxx(R), Anaprox(R), Arthro fore. Tumor necrosis factor (TNF) is a key proinflammatory tec(R), Bextra(E), Cataflam(R), Clinoril(R), DayPro.(R), Dolobid(R), cytokine released by a number of cell types, particularly Feldenece, Indocine, Mobic E), Motrine), Negprelen(R), activated macrophages and monocytes. Additional details NaprosyncE), Ponstel(R), Relafen(R), Toradol(R). regarding the manufacture and use of TNF-C. antagonists are 0159. In an embodiment, the present compositions may available in U.S. Patent Application Publication No. U.S. further comprise an analgesic, antipyretic, and/or anti-in 2003/0157061 A1, which is incorporated herein by refer flammatory therapeutic agent. For example, the composition CCC. may further comprise one or more of aspirin, Sodium Sali 0163 Preferred TNF-C. antagonists for the present dis cylate, choline magnesium trisalicylate, Salsalate, diflunisal, closure include ENBREL(R) (etanercept) from Wyeth-Ayerst SulfaSalazine, Olsalazine, acetaminophen (paracetamol), for Laboratories/Immunex; REMICADE(E), infiximab, which is example Tylenol PM, indomethacin, Sulindac, tolmetin, an anti-TNF chimeric Mab (Centocor; Johnson & Johnson); diclofenac, ketorolac, ibuprofen, naproxen, flurbiprofen, anti-TNF-C, D2E7 human Mab (Cambridge antibody Tech ketoprofen, fenoprofen, oxaprozin, mefenamic acid, nology); CDP-870, which is a PEGylated antibody fragment meclofenamic acid, piroXicam, meloxicam, nabumetone, (Celltech); CDP-571; Humicade, which is a humanized Mab refecoxib, celecoxib, etodolac, and nimeSulide. For described in U.S. Pat. No. 5,994,510 (Celltech); PEGylated example, the present compositions may comprise an opioid soluble TNF-C. Receptor-1 (Amgen); TBP-1, which is a TNF antagonist (Such as naltrexone), an opioid agonist (Such as binding protein (Ares Serono); PASSTNF-alpha(R), which is oxycodone or hydrocodone), and an analgesic (Such as an anti-TNF-C. polyclonal antibody (Verigen); AGT-1, acetaminophen). which is a mixture of three anti-cytokine antibodies to US 2006/0009478 A1 Jan. 12, 2006

IFN-alpha, IFN-gamma, and TNF (Advanced Biotherapy drug. The effective amount of the opioid antagonist and the Concepts); TENEFUSE(R), ienercept, which is a TNFR-Ig opioid agonist can be present at a level that potentiates the fusion protein (Roche); CytoTAB(R(Protherics); TACE, effectiveness of the anti-rheumatic drug. Specific dosage which is a small molecule TNF-C. converting enzyme inhibi levels for anti-rheumatic drugs that can be used herein as tor (Immunex); small molecule TNF mRNA synthesis given, inter alia, are included, for example, in the “Physi inhibitor (Nereus); PEGylated p75TNFR Fc mutein (Immu cians’ Desk Reference”, 2003 Edition (Medical Economics nex); and TNF-C. antisense inhibitor. Data Production Company, Montvale, N.J.) as well as in 0164. With regard to dosage levels, the TNF-C. antagonist other reference WorkS. is present at an amount effective to inhibit progression or 0167. In an embodiment, the present compositions fur reduce damage from an arthritic condition or a chronic ther comprise at least one anticonvulsant or anti-epileptic condition associated with inflammation. Alternatively, the agent. Any therapeutically effective anticonvulsant may be TNF-C. antagonist is present in an amount that is not used according to the present disclosure. For extensive effective to inhibit progression or reduce damage alone but listings of anticonvulsants, See, e.g., Goodman and Gilman's is effective to inhibit progression or reduce damage in “The Pharmaceutical Basis Of Therapeutics', 8th ed., combination with an opioid agonist and opioid antagonist McGraw-Hill, Inc. (1990), pp. 436-462, and “Remington's according to the present disclosure. This amount is at a level Pharmaceutical Sciences”, 17th ed., Mack Publishing Com corresponding to the generally recommended adult human pany (1985), pp. 1075-1083 (the disclosures of which are dosages for a particular TNF-C. antagonist. The effective incorporated herein by reference). Representative anticon pain-alleviating amount of the opioid antagonist and the Vulsants that can be used herein include lamotrigine, gaba opioid agonist can be present at a level that potentiates the pentin, Valproic acid, topiramate, famotodine, phenobar effectiveness of a TNF-C. antagonist. Specific dosage levels bital, diphenylhydantoin, phenyloin, mephenyloin, ethotoin, for TNF-C. antagonists that can be used herein as given, inter mephobarbital, primidone, carbamazepine, ethoSuximide, alia, are included, for example, in the “Physicians Desk methSuximide, phensuXimide, trimethadione, benzodiaz Reference”, 2003 Edition (Medical Economics Data Pro epine, phenacemide, acetazolamide, progabide, clonazepam, duction Company, Montvale, N.J.) as well as in other divalproex Sodium, magnesium Sulfate injection, methar reference works including Goodman and Gilman’s “The bital, paramethadione, phenyloin Sodium, Valproate Sodium, Pharmaceutical Basis of Therapeutics” and “Remington's clobazam, Sulthiame, dilantin, diphenylan and L-5-hydrox Pharmaceutical Sciences,” the disclosure of all are incor ytryptophan. Currently marketed anticonvulant/anti-epilep porated herein by reference. AS is well known to one of tic drugs include Keppra(E), Lamictolf), Neurontin(R), Tegre ordinary skill in the art, there can be a wide variation in the tol(R), Carbatrol(R), Topiramate(R), Trileptal(R), and dosage level of the TNF-C. antagonist, wherein the dosage Zonegrane). level depends to a large extent on the specific TNF-C. 0168 With regard to dosage levels, the anticonvulsant is antagonist being administered. These amounts can be deter present at a pain-alleviating amount or an amount that is not mined for a particular drug combination, in accordance with pain-alleviating alone but is pain-alleviating in combination the present disclosure, by employing routine experimental with an opioid agonist and opioid antagonist according to testing. the present disclosure. This amount is at a level correspond 0.165. In an embodiment, the present compositions fur ing to the generally recommended adult human dosages for ther comprise at least one anti-rheumatic drug. Anti-rheu a particular anticonvulsant. The effective pain-alleviating matic drugs include those referred to as Disease-modifying amount of the opioid antagonist and the opioid agonist can antirheumatic drugs (DMARDs). Anti-rheumatic drugs be present at a level that potentiates the pain-alleviating include methotrexate (RHEUMATREX, TREXALL), effectiveness of the anticonvulsant. Specific dosage levels leflunomide (ARAVA), D-Penicillamine, Sulfasalazine, gold for anticonvulsants that can be used herein as given, inter therapy, minocycline, azathioprine, hydroxychloroquine alia, are included, for example, in the “Physicians Desk (PLAQUENIL) and other antimalarials, cyclosporine and Reference”, 2003 Edition (Medical Economics Data Pro biologic agents. Biologic response modifiers, often referred duction Company, Montvale, N.J.) as well as in other to as biologic agents or Simply biologics, are designed to reference works including Goodman and Gilman’s “The either inhibit or Supplement immune System components Pharmaceutical Basis of Therapeutics” and “Remington's called cytokines. Cytokines play a role in either fueling or Pharmaceutical Sciences,” the disclosure of all are incor Suppressing the inflammation that causes damage in RA and porated herein by reference. AS is well known to one of Some other diseases. The four biologics currently approved ordinary skill in the art, there can be a wide variation in the for RA all work by inhibiting inflammatory cytokines. dosage level of the anticonvulsant, wherein the dosage level Adalimumab (HUMIRA), etanercept (ENBREL) and inflix depends to a large extent on the Specific anticonvulsant imab (REMICADE) work to inhibit a cytokine called tumor being administered. These amounts can be determined for a necrosis factor (TNF). Anakinra (KINERET) blocks the particular drug combination, in accordance with this present action of the cytokine interleukin-1 (IL-1). disclosure, by employing routine experimental testing. 0166 With regard to dosage levels, the anti-rheumatic 0169. The compositions presented herein may be com drug is present at an amount that attenuates a Symptom or pounded, for example, with the usual non-toxic, pharma Sign of rheumatism or an amount that does not attenuate ceutically acceptable excipients, carriers, diluents or other Such a Symptom or sign alone but does attenuate Such a adjuvants. The choice of adjuvants will depend upon the Symptom or sign in combination with an opioid agonist and active ingredients employed, the physical form of the com opioid antagonist according to the present disclosure. This position, the route of administration, and other factors. amount is at a level corresponding to the generally recom 0170 The excipients, binders, carriers, and diluents mended adult human dosages for a particular anti-rheumatic which can be used include water, glucose, lactose, natural US 2006/0009478 A1 Jan. 12, 2006

SugarS Such as Sucrose, glucose, or corn Sweeteners, Sorbitol, pounds include, by way of example and without limitation, natural and Synthetic gums. Such as gum acacia, tragacanth, acacia, alginic acid, carboxymethylcellulose Sodium, poly Sodium alginate, and gum arabic, gelatin, mannitol, Starches (Vinylpyrrolidone), compressible Sugar (e.g., NuTab), eth Such as Starch paste, corn Starch, or potato Starch, magne ylcellulose, hydroxypropyl methylcellulose, gelatin, liquid sium trisilicate, talc, keratin, colloidal Silica, urea, Stearic glucose, methylcellulose, povidone and pregelatinized acid, magnesium Stearate, dibasic calcium phosphate, crys Starch and other materials known to one of ordinary skill in talline cellulose, methyl cellulose, carboxymethyl cellulose, the art. polyethylene glycol, waxes, glycerin, and Saline Solution, 0179 When needed, binders may also be included in the among others. dosage forms. Exemplary binders include acacia, tragacanth, 0171 Suitable dispersing or Suspending agents for aque gelatin, Starch, cellulose materials. Such as methyl cellulose, ous Suspensions include Synthetic and natural gums Such as HPMC, HPC, HEC and sodium carboxy methyl cellulose, tragacanth, acacia, alginate, dextran, Sodium carboxymeth alginic acids and Salts thereof, polyethylene glycol, guar ylcellulose, methylcellulose, polyvinylpyrrollidone or gela gum, polysaccharide, bentonites, Sugars, invert Sugars, tin. poloxamers (PLURONICTM F68, PLURONICTM F127), col 0172 The dosage forms can also comprise one or more lagen, albumin, gelatin, cellulosicS in nonaqueous Solvents, acidifying agents, adsorbents, alkalizing agents, antiadher combinations thereof and others known to those skilled in ents, antioxidants, binders, buffering agents, colorants, com the art. Other binders include, for example, polypropylene plexing agents, diluents or fillers, direct compression excipi glycol, polyoxyethylene-polypropylene copolymer, poly ents, disintegrants, flavorants, fragrances, glidants, ethylene ester, polyethylene Sorbitan ester, polyethylene lubricants, opaquants, plasticizers, polishing agents, preser oxide, combinations thereof and other materials known to Vatives, Sweetening agents, or other ingredients known for one of ordinary skill in the art. use in pharmaceutical preparations. 0180 Buffering agents are compounds used to resist 0173 Acidifying agents are a compound used to provide changes in pH upon dilution or addition of acid or alkali. an acidic medium for product Stability. Such compounds Such compounds include, by way of example and without include, by way of example and without limitation, acetic limitation, potassium metaphosphate, potassium phosphate, acid, amino acid, citric acid, fumaric acid and other alpha monobasic Sodium acetate and Sodium citrate anhydrous and hydroxy acids, hydrochloric acid, ascorbic acid, nitric acid, dihydrate and other materials known to one of ordinary skill phosphoric acid, and others known to those skilled in the art. in the art. 0.174. Adsorbents are agents capable of holding other 0181 Sweetening agents are compounds used to impart molecules onto their Surface by physical or chemical Sweetness to a preparation. Such compounds include, by (chemisorption) means. Such compounds include, by way of way of example and without limitation, aspartame, dextrose, example and without limitation, powdered and activated glycerin, mannitol, Saccharin Sodium, Sorbitol, Sucrose, and charcoal, Zeolites, and other materials known to one of other materials known to one of ordinary skill in the art. ordinary skill in the art. 0182 Diluents or fillers are inert Substances used to 0.175 Alkalizing agent are compounds used to provide an create the desired bulk, flow properties, and compression alkaline medium for product Stability. Such compounds characteristics in the preparation of Solid dosage forms. include, by way of example and without limitation, ammo Such compounds include, by way of example and without nia Solution, ammonium carbonate, diethanolamine, mono limitation, dibasic calcium phosphate, kaolin, lactose, dex ethanolamine, potassium hydroxide, Sodium borate, Sodium trose, magnesium carbonate, Sucrose, mannitol, microcrys carbonate, Sodium bicarbonate, Sodium hydroxide, trietha talline cellulose, powdered cellulose, precipitated calcium nolamine, and trolamine and others known to those skilled carbonate, calcium Sulfate, Sorbitol, and Starch and other in the art. materials known to one of ordinary skill in the art. 0176 Antiadherent are agents that prevents the sticking 0183 Direct compression excipients are compounds used of Solid dosage formulation ingredients to punches and dies in compressed Solid dosage forms. Such compounds in a tableting machine during production. Such compounds include, by way of example and without limitation, dibasic include, by way of example and without limitation, magne calcium phosphate (e.g., Ditab) and other materials known sium Stearate, talc, calcium Stearate, glyceryl behenate, to one of ordinary skill in the art. PEG, hydrogenated vegetable oil, mineral oil, Stearic acid 0.184 Disintegrants are compounds used in Solid dosage and other materials known to one of ordinary skill in the art. forms to promote the disruption of the Solid mass into 0177 Antioxidants are agents which inhibits oxidation Smaller particles which are more readily dispersed or dis and thus is used to prevent the deterioration of preparations Solved. Exemplary disintegrants include, by way of example by the oxidative process. Such compounds include, by way and without limitation, Starches Such as corn Starch, potato of example and without limitation, ascorbic acid, ascorbyl Starch, pre-gelatinized and modified Starches thereof, Sweet palmitate, butylated hydroxyanisole, butylated hydroxytolu eners, clayS. Such as bentonite, low Substituted hydroxypro ene, hypophophorous acid, monothioglycerol, propyl gal pyl cellulose, microcrystalline cellulose (e.g., Avicel), methyl cellulose, carboxymethylcellulose calcium, Sodium late, Sodium ascorbate, Sodium bisulfite, Sodium formalde carboxymethylcellulose, alginic acid, Sodium alginate, cel hyde sulfoxylate and sodium metabisulfite and other lulose polyacrilin potassium (e.g., Amberlite), alginates, materials known to one of ordinary skill in the art. Sodium Starch glycolate, gums, agar, guar, locust bean, 0.178 Binders are substances used to cause adhesion of karaya, Xanthan, pectin, tragacanth, agar, bentonite, and powder particles in Solid dosage formulations. Such com other materials known to one of ordinary skill in the art. US 2006/0009478 A1 Jan. 12, 2006

0185. Glidants are agents used in Solid dosage formula 0193 Exemplary preservatives include materials that tions to promote flowability of the solid mass. Such com inhibit bacterial growth, Such as Nipagin, Nipasol, alcohol, pounds include, by way of example and without limitation, antimicrobial agents, benzoic acid, Sodium benzoate, benzyl colloidal Silica, cornstarch, talc, calcium Silicate, magne alcohol, Sorbic acid, parabens, isopropyl alcohol and others sium Silicate, colloidal Silicon, tribasic calcium phosphate, known to one of ordinary skill in the art. Silicon hydrogel and other materials known to one of ordi nary skill in the art. 0194 Solid dosage forms of the present methods and materials can also employ one or more Surface active agents 0186 Lubricants are substances used in solid dosage or coSolvents that improve wetting or disintegration of the formulations to reduce friction during compression. Such core and/or layer of the Solid dosage form. compounds include, by way of example and without limi tation, Sodium oleate, Sodium Stearate, calcium Stearate, Zinc 0.195 Plasticizers can include, by way of example and Stearate, magnesium Stearate, polyethylene glycol, talc, min without limitation, low molecular weight polymers, oligo eral oil, Stearic acid, Sodium benzoate, Sodium acetate, mers, copolymers, oils, Small organic molecules, low Sodium chloride, and other materials known to one of molecular weight polyols having aliphatic hydroxyls, ester ordinary skill in the art. type plasticizers, glycol ethers, poly(propylene glycol), multi-block polymers, Single block polymers, low molecular 0187. Opaquants are compounds used to render a coating weight poly(ethylene glycol), citrate ester-type plasticizers, opaque. An opaquant may be used alone or in combination triacetin, propylene glycol and glycerin. Such plasticizers with a colorant. Such compounds include, by way of can also include ethylene glycol, 1,2-butylene glycol, 2,3- example and without limitation, titanium dioxide, talc and butylene glycol, Styrene glycol, diethylene glycol, triethyl other materials known to one of ordinary skill in the art. ene glycol, tetraethylene glycol and other poly(ethylene 0188 Polishing agents are compounds used to impart an glycol) compounds, monopropylene glycol monoisopropyl attractive Sheen to Solid dosage forms. Such compounds ether, propylene glycol monoethyl ether, ethylene glycol include, by way of example and without limitation, carnauba monoethyl ether, diethylene glycol monoethyl ether, Sorbitol wax, white wax and other materials known to one of lactate, ethyl lactate, butyl lactate, ethylglycolate, dibutylse ordinary skill in the art. bacate, acetyltributylcitrate, triethyl citrate, acetyl triethyl citrate, tributyl citrate and allyl glycolate. All Such plasti 0189 Colorants are compounds used to impart color to cizers are commercially available from Sources Such as Solid (e.g., tablets) pharmaceutical preparations. Such com Aldrich or Sigma Chemical Co. The PEG based plasticizers pounds include, by way of example and without limitation, are available commercially or can be made by a variety of FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, methods, such as disclosed in Poly(ethylene glycol) Chem FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, istry. Biotechnical and Biomedical Applications (J. M. Har D&C Red No. 8, caramel, ferric oxide, other FD&C dyes ris, Ed., Plenum Press, NY) the disclosure of which is and natural coloring agentS Such as grape skin extract, beet hereby incorporated by reference. red powder, beta-caroteine, annato, carmine, turmeric, paprika, and other materials known to one of ordinary skill 0196. Solid dosage forms of the present methods and in the art. The amount of coloring agent used will vary as materials can also include oils, for example, fixed oils, Such desired. as peanut oil, Sesame oil, cottonseed oil, corn oil and olive oil; fatty acids, Such as oleic acid, Stearic acid and isoStearic 0.190 Flavorants are compounds used to impart a pleas acid; and fatty acid esters, Such as ethyl oleate, isopropyl ant flavor and often odor to a pharmaceutical preparation. myristate, fatty acid glycerides and acetylated fatty acid Exemplary flavoring agents or flavorants include Synthetic glycerides. It can also be mixed with alcohols, Such as flavor oils and flavoring aromatics and/or natural oils, ethanol, isopropanol, hexadecyl alcohol, glycerol and pro extracts from plants, leaves, flowers, fruits and So forth and pylene glycol, with glycerol ketals, Such as 2,2-dimethyl-1, combinations thereof. These may also include cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay oil, anise 3-dioxolane-4-methanol; with ethers, Such as poly(ethyl oil, eucalyptus, thyme oil, cedar leave oil, oil of nutmeg, oil eneglycol) 450, with petroleum hydrocarbons, such as of Sage, oil of bitter almonds and cassia oil. Other useful mineral oil and petrolatum; with water, or with mixtures flavors include Vanilla, citrus oil, including lemon, orange, thereof; with or without the addition of a pharmaceutically grape, lime and grapefruit, and fruit essences, including Suitable Surfactant, Suspending agent or emulsifying agent. apple, pear, peach, Strawberry, raspberry, cherry, plum, pine 0.197 Soaps and synthetic detergents may be employed apple, apricot and So forth. Flavors which have been found as Surfactants and as Vehicles for the Solid pharmaceutical to be particularly useful include commercially available compositions. Suitable Soaps include fatty acid alkali metal, orange, grape, cherry and bubble gum flavors and mixtures ammonium, and triethanolamine Salts. Suitable detergents thereof. The amount of flavoring may depend on a number include cationic detergents, for example, dimethyl dialkyl of factors, including the organoleptic effect desired. Flavors ammonium halides, alkyl pyridinium halides, and alky will be present in any amount as desired by those skilled in lamine acetates, anionic detergents, for example, alkyl, aryl the art. Particularly contemplated flavors are the grape and and olefin Sulfonates, alkyl, olefin, ether and monoglyceride cherry flavors and citrus flavorS Such as orange. Sulfates, and SulfoSuccinates, nonionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and 0191 Complexing agents include for example EDTA poly(oxyethylene)-block-poly(oxypropylene) copolymers; disodium or its other Salts and other agents known to one of and amphoteric detergents, for example, alkyl beta-amino ordinary skill in the art. propionates and 2-alkylimidazoline quaternary ammonium 0.192 Exemplary fragrances include those generally Salts, and others known to one of ordinary skill in the art, and accepted as FD&C grade. mixtures thereof. US 2006/0009478 A1 Jan. 12, 2006 22

0198 A water soluble coat or layer can be formed to in Solvent Such as methylene chloride, evaporated to the Surround a Solid dosage form or a portion thereof. The water desired Viscosity, and then applied to backing material to Soluble coat or layer can either be inert or drug-containing. provide a patch. Such a coat or layer will generally comprise an inert and 0202 For intravenous, intramuscular, subcutaneous, non-toxic material which is at least partially, and optionally intrathecal, epidural, perineural or intradermal administra Substantially completely, Soluble or erodible in an environ tion, the active ingredients may be combined with a Sterile ment of use. Selection of Suitable materials will depend upon aqueous Solution. The Solution may be isotonic with the the desired behavior of the dosage form. A rapidly dissolving blood of the recipient. Such formulations may be prepared coat or layer will be Soluble in the buccal cavity and/or upper by dissolving one or more Solid active ingredients in water GI tract, Such as the Stomach, duodenum, jejunum or upper containing physiologically compatible Substances Such as Small intestines. Exemplary materials are disclosed in U.S. Sodium chloride, glycine, or others known to those skilled in Pat. No. 4,576,604 to Guittard et al. and U.S. Pat. No. the art, and/or having a buffered pH compatible with physi 4,673,405 to Guittard et al., and U.S. Pat. No. 6,004,582 to ological conditions to produce an aqueous Solution, and/or Faour et al. and the text Pharmaceutical Dosage Forms. rendering the Solution Sterile. The formulations may be Tablets Volume I, 2" Edition. (A. Lieberman. ed. 1989, present in unit dose containerS Such as Sealed ampoules or Marcel Dekker, Inc.), the disclosures of which are hereby Vials. incorporated by reference. In Some embodiments, the rap 0203 For topical (e.g., dermal or subdermal) or depot idly dissolving coat or layer will be Soluble in Saliva, gastric administration, the active ingredients may be formulated juices, or acidic fluids. with oils. Such as cottonseed, hydrogenated castor oil and 0199 Materials which are suitable for making the water mineral oil; Short chain alcohols as chlorobutanol and benzyl Soluble coat or layer include, by way of example and without alcohol; also including polyethylene glycols, polySorbates, limitation, water Soluble polysaccharide gums Such as car polymerS Such as Sucrose acetate isobutyrate, caboxymetho rageenan, fucoidan, gum ghatti, tragacanth, arabinogalactan, cellusose and acrylates, bufferS Such as dihydrogen phos pectin, and Xanthan, water-Soluble Salts of polysaccharide phate, SaltS Such as Sodium chloride and calcium phosphate; gums Such as Sodium alginate, Sodium tragacanthin, and and other ingredients included but not exclusive to povi Sodium gum ghattate; water-Soluble hydroxyalkylcellulose done, lactose monohydrate, magnesium Stearate, myristyo wherein the alkyl member is straight or branched of 1 to 7 gamma-picolinium; and water. carbons such as hydroxymethylcellulose, hydroxyethylcel 0204 A Solid dosage form of the present methods and lulose, and hydroxypropylcellulose, Synthetic water-Soluble materials can be coated with a finish coat as is commonly cellulose-based lamina formerS Such as methyl cellulose and done in the art to provide the desired Shine, color, taste or its hydroxyalkyl methylcellulose cellulose derivatives such other aesthetic characteristics. Materials Suitable for prepar as a member Selected from the group consisting of hydroxy ing the finish coat are well known in the art and found in the ethyl methylcellulose, hydroxypropyl methylcellulose, and disclosures of many of the references cited and incorporated hydroxybutyl methylcellulose, croScarmellose Sodium; by reference herein. other cellulose polymerS Such as Sodium carboxymethylcel lulose, and other materials known to those skilled in the art. 0205 Various other components, in some cases not oth Other lamina-forming materials that can be used for this erwise listed above, can be added to the present formulation purpose include poly(Vinyl alcohol), poly(ethylene oxide), for optimization of a desired active agent release profile gelatin, glucose and Saccharides. The water Soluble coating including, by way of example and without limitation, glyc can comprise other pharmaceutical excipients that may or erylmonoStearate, nylon, cellulose acetate butyrate, d.l-poly may not alter the way in which the water Soluble coating (lactic acid), 1,6-hexanediamine, diethylenetriamine, behaves. The artisan of ordinary skill will recognize that the Starches, derivatized Starches, acetylated monoglycerides, above-noted materials include film-forming polymers. gelatin coacervates, poly (styrene-maleic acid) copolymer, glycowax, castor wax, Stearyl alcohol, glycerol palmito 0200 A water soluble coat or layer can also comprise Stearate, poly(ethylene), poly(Vinyl acetate), poly(Vinyl hydroxypropyl methylcellulose, which is supplied by Dow chloride), 1,3-butylene-glycoldimethacrylate, ethylenegly under its Methocel E-15 trademark. The materials can be col-dimethacrylate and methacrylate hydrogels. prepared in Solutions having different concentrations of polymer according to the desired Solution Viscosity. For 0206. The compositions for use in the methods of the example, a 2% W/V aqueous solution of MethocelTM E-15 present disclosure can be formulated in capsules, tablets, caplets, or pills. Such capsules, tablets, caplets, or pills of the has a viscosity of about 13-18 cps at 20° C. present inflammatory pain-alleviating compositions can be 0201 For transcutaneous or transdermal administration, coated or otherwise compounded to provide a dosage form the compounds may be combined with skin penetration affording the advantage of prolonged action. For example, enhancerS Such as propylene glycol, polyethylene glycol, the tablet or pill can comprise an inner dosage and an outer isopropanol, ethanol, oleic acid, N-methylpyrrollidone, or dosage component, the latter being in the form of an others known to those skilled in the art, which increase the envelope over the former. The two components can be permeability of the Skin to the compounds, and permit the Separated by an enteric layer which Serves to resist disinte compounds to penetrate through the skin and into the gration in the Stomach and permits the inner component to bloodstream. The compound/enhancer compositions also pass intact into the duodenum or to be delayed in release. A may be combined additionally with a polymeric Substance variety of materials can be used for Such enteric layers or Such as ethylcellulose, hydroxypropyl cellulose, ethylene/ coatings, Such materials including a number of polymeric Vinylacetate, or others known to those skilled in the art, to acids and mixtures of polymeric acids with Such materials as provide the composition in gel form, which can be dissolved shellac, cetyl alcohol and cellulose acetate. Similarly, the US 2006/0009478 A1 Jan. 12, 2006 23 carrier or diluent may include any Sustained release material compositions are in the form of a topical, intravenous, known in the art, Such as glyceryl monoStearate or glyceryl intrathecal, epidural, perineural, or oral formulation. More distearate, alone or mixed with a wax. The formulations of preferably, Such compositions are in the form of an intrath the present methods and materials may be formulated So as ecal, epidural or perineural formulation. Even more prefer to provide quick, Sustained, or delayed release of the active ably, Such compositions are in the form of an intravenous ingredient after administration to the patient by employing formulation. Most preferably, Such compositions are in the procedures well known in the art. form of an oral formulation. 0207 Controlled release or sustained-release dosage 0214. The present methods and materials are additionally forms, as well as immediate release dosage forms are advantageous because they can be used to maintain or Specifically contemplated. Controlled release or Sustained enhance (e.g., increase) analgesic potency of the opioid release as well as immediate release compositions in liquid agonists without Substantially increasing the adverse side forms in which a therapeutic agent may be incorporated for effects in humans associated with that dose of agonist, administration orally or by injection are also contemplated. including attenuating one or more adverse effects. For example, the present methods and compositions may be 0208. The pharmaceutical compositions or dosage forms employed in human Subjects without significant increases, of the present methods and materials may be used in the including attenuating in incidents of eye disorders, gas form of a pharmaceutical preparation which contains one or trointestinal disorders (such as upper abdominal pain, con more opioid antagonists in combination with one or more Stipation, diarrhea, nausea, and vomiting), general disorders opioid agonists. and conditions (Such as lethargy), nervous System disorders 0209. It has previously been discovered that some opioid (Such as dizziness, , Sedation, and Sommolence), antagonists undesirably bind Significantly to certain phar psychiatric disorders (Such as euphoric mood), and skin and maceutical excipients, including during the preparation of Subcutaneous tissue disorders (such as pruritus). For com dosage forms of antagonist of 1 mg or less, 0.5 mg or leSS positions and methods as described that enhance analgesic or less, 0.1 mg or less, 0.01 mg or less, or 0.001 mg or less. potency of the opioid agonist, it is advantageous that adverse Those pharmaceutical excipients generally cause an incom Side effects are not increased with that enhanced e.g., plete amount of the opioid antagonist to be released from a increased) potency. dosage form, within a particular time allotted for release. For 0215. The following examples are provided for illustra example, when naltrexone hydrochloride in Solution was tive purposes and are not to be construed to limit the Scope mixed with croScarmellose Sodium in Suspension, the cros of the claims in any manner whatsoever. For example, carmellose Sodium bound more than 90% of the naltrexone Example 6 describes Studies using methods and materials hydrochloride. Accordingly, opioid antagonists must be comprising opioid antagonists, including combinations of tested with pharmaceutical excipients, So as to ensure that opioid agonists and antagonists, for the treatment of back the excipient does not bind the opioid antagonist to a pain. Examples 1-5 describe correlative Studies. Significant degree. Excipients, for example, binders, disin tegrants, glidants, lubricants, or acidifiers, as well as proceSS EXAMPLE 1. conditions, Such as pH, should be Selected with this in mind. A. 0210. The compositions present herein for alleviating the 0216) In a clinical study, the effects of an exemplary Symptoms or signs of arthritic conditions, chronic conditions opioid agonist oxycodone in combination with an exemplary asSociated with inflammation or chronic pain can be admin opioid antagonist naltrexone were evaluated in Subjects with istered from about one time daily to about Six times daily, moderate to Severe chronic pain due to an exemplary two times daily to about four times daily, or one time daily arthritic condition Osteoarthritis of the hip or knee. to about two times daily. 0217. A clinical study was designed as follows: (1) to 0211 Pain-alleviating compositions, including inflam evaluate the efficacy and Safety of combinations of oxyc matory pain-alleviating compositions, presented herein pref odone (oxy) and naltrexone (ntx) administered twice daily erably comprise at least one colloidal dispersion System, and four times daily relative to oxycodone administered four additive or preservative, diluent, binder, plasticizer, or slow times daily while maintaining the Same total daily oxyc release agent. odone dose, and (2) to evaluate the frequency and Severity of opioid withdrawal in patients who received combinations 0212. It should be understood that compounds used in the of oxycodone and naltrexone compared to those patients art of pharmaceutical formulation generally Serve a variety who received oxycodone. of functions or purposes. Thus, whether a compound named 0218. A multicenter, randomized, double-blind, active herein is mentioned only once or is used to define more than and placebo-controlled, dose escalation, clinical Study was one term herein, its purpose or function should not be designed and conducted. The Study evaluated the efficacy construed as being limited Solely to the named purpose(s) or and Safety of an oral formulation of oxycodone and naltr function(s). eXOne relative to oxycodone over a 3-week period in patients 0213 The present pain-alleviating compositions, includ with chronic pain due to Osteoarthritis of the hip or knee. A ing inflammatory pain-alleviating compositions, may be in total of 360 patients were enrolled into four treatment admixture with an organic or inorganic carrier or excipient groups: two groups for combinations of oxycodone and Suitable for administration in enteral or parenteral applica naltrexone, a group for oxycodone alone, and a group for tions, Such as orally, topically, transdermally, by inhalation placebo. During a 4- to 7-day washout period, patients Spray, rectally, by Subcutaneous, intravenous, intramuscular, Stopped taking all of their pain medication other than Subcutaneous, intrathecal, epidural, perineural, intradermal, acetaminophen (500 mg every 4-6 hours PRN (a maximum intraocular injection or infusion techniques. Preferably, Such of 5 caplets per day)). US 2006/0009478 A1 Jan. 12, 2006 24

0219. A daily diary was to be utilized to record overall inclusion/exclusion criteria. Baseline functional assessments pain intensity (PI) and other signs and Symptoms. The were conducted with the SF-12 Health Survey as shown in patient was enrolled in the study if: (1) the mean value of the Table 1 and the Western Ontario and MacMaster Universi diary PI over the last 2 days of the 4- to 7-day baseline period was 25; (2) the confirmatory PI obtained at the ties Osteoarthritis Index (WOMAC) as shown in Table 2 baseline clinic visit was also 25; and, (3) the patient met all below before the initiation of study medication.

TABLE 1. The SF-12v2 TM Health Survey Instructions for Completing the Questionnaire Please answer every question. Some questions may look like others, but each one is different. Please take the time to read and answer each question carefully by filling in the bubble that best represents your response. EXAMPLE This is for your review. Do not answer this question. The questionnaire begins with the section Your Health in General below. For each question you will be asked to fill in a bubble in each line: 1. How strongly do you agree or disagree with each of the following statements? Strongly Strongly agree Agree Uncertain Disagree disagree a) I enjoy listening to O O O O O music. b) I enjoy reading O O O O O magazines. Please begin answering the questions now. Your Health in General 1. In general, would you say your health is: Excellent Very good Good Fair Poor O1 O2 Os O4 Os GH1 2. The following questions are about activities you might do during a typical day. Does your health now limit you in these activities? If so, how much? Yes, limited Yes, limited No, not limited a lot a little at all a) Moderate activities, O1 O2 Os PFO2 such as moving a table, pushing a vacuum cleaner, bowling, or playing golf b) Climbing several O1 O2 Os PFO4 flights of stairs 3. During the past week, how much of the time have you had any of the following problems with your work or other regular daily activities as a result of your physical health? All of Most of Some of A little of None of the time the time the time the time the time a) Accomplished less O1 O2 Os O4 O RP2 than you would like b) Were limited in the O1 O2 Os O4 O RP3 kind of work or other activities 4. During the past week, how much of the time have you had any of the following problems with your work or other regular daily activities as a result of any emotional problems (such as feeling depressed or anxious)?

All of Most of Some of A little of None of the time the time the time the time the time a) Accomplished less O1 O2 Os O4 O RE2 than you would like b) Did work or O1 O2 Os O4 Os RE3 US 2006/0009478 A1 Jan. 12, 2006 25

TABLE 1-continued The SF-12v2 TM Health Survey other activities less carefully than usual 5. During the past week, how much did pain interfere with your normal work (including both work outside the home and housework)? Not at all A little bit Moderately Quite a bit Extremely O1 O2 Os O4 Os BP2 6. These questions are about bow you feel and how things have been with you during the past week. For each question, please give the one answer that comes closest to the way you have been feeling. How much of the time during the past week . .

All of Most of Some of A little of None of the time the time the time the time the time a) have you felt calm O1 O2 Os O4 Os MH3 and peaceful? b) did you have a lot O1 O2 Os O4 Os VT2 of energy? c) have you felt O1 O2 Os O4 Os MH4 downhearted and depressed? 7. During the past week, how much of the time has your physical health or emotional problems interfered with your social activities (like visiting friends, relatives, etc.)? All of Most of Some of A little None of the time the time the time of the time the time O1 O2 Os O4 Os SF2 THANK YOU FOR COMPLETING THIS QUESTIONNAIRE

O220) TABLE 2-continued TABLE 2

WOMAC OSTEOARTHRITIS INDEX WOMAC OSTEOARTHRITIS INDEX Directions: Please refer to the instructions provided to you for completion of the following questions. Section A Section B PAIN STIFFNESS Think about the pain you felt in your (study joint) caused by your arthritis during the last 48 hours. (Please mark your answers with an "x").fift Think about the stiffness (not pain) you felt in your (study joint) caused by your arthritis during the last 48 hours. Stiffness is a sensa QUESTION: How much pain have you had... STUDY tion of decreased ease in moving your joint. (Please mark your answers COORDINATOR with an "x"). 1. when walking on a flat surface? USE ONLY 6. How severe has your stiffness been after you No Extreme first woke up in the morning? Pain Pain No Extreme --- - mn 2. when going up or down stairs? Stiffness Stiffness 7. How severe has your stiffness been after sitting or lying down, or while resting later in the day? 3. at night while in bed? (that is - pain No Extreme that disturbs your sleep) Stiffness Stiffness

Section C DIFFICULTY PERFORMING DALY ACTIVITIES

5. while standing? No Extreme Pain US 2006/0009478 A1 Jan. 12, 2006 26

TABLE 2-continued TABLE 2-continued

WOMAC OSTEOARTHRITIS INDEX WOMAC OSTEOARTHRITIS INDEX

Think about the difficulty you had in doing the following daily physical activities caused by your arthritis in your (study joint) 21. while sitting? during the last 48 hours. By this we mean your ability to move around No Extreme and take care of yourself. (Please mark your answers with an "x"). Difficulty Difficulty 22. when getting on or off the toilet? QUESTION: How much difficulty have you had... STUDY No Extreme COORDINATOR Difficulty Difficulty 8. when going down the stairs? USE ONLY No Extreme 23. while doing heavy household chores? Difficulty Difficulty No Extreme Difficulty Difficulty 9. when going up the stairs? N O Extreme 24. while doing light household chores? Difficu y H D 1culty No Extreme Difficulty Difficulty 10. when getting up from a sitting position? Extreme Difficulty ifficulty 11. while standing? Extreme Difficulty ifficulty 0221) Patients were randomly assigned to one of the four treatment groups as shown in Table 3. 12. when bending to the floor? No Ex ele Difficu y H D iculty

13. when walking on a flat surface? N O Extreme Difficu y Difficu 14. getting in or out of a car, or getting on or off a bus? N O Extreme Difficu y H Difficu 15. while going shopping? O Extreme Difficu y H D Cl

Think about the difficulty you had in doing the following daily physical activities caused by your arthritis in your (study joint) during the last 48 hours. By this we mean your ability to move around and take care of yourself. (Please mark your answers with an "x"). QUESTION: How much difficulty have you had... STUDY COORDINATOR 16. when putting on your socks or pantyhose or USE ONLY stockings? No Extreme Difficulty Difficulty 17. when getting out of bed? N O Extreme Difficu y H D 1culty 18. when taking off your socks or pantyhose or stockings? No Extreme Difficulty Difficulty 19. while lying in bed? No Extreme Difficulty Difficulty 20. when getting in or Out of the bathtub? N O Extreme Difficu y H D 1culty US 2006/0009478 A1 Jan. 12, 2006

TABLE 3

Treatment Week 1 Week 2 Week 3 Group (Days 1-3) (Days 4-8) (Days 1-8) (Days 1-8) A. (OXY 5 mg + (OXY 10 mg + (OXY 15 mg + (OXY 20 mg + NTX 0.001 mg) NTX 0.001 mg) NTX 0.001 mg) NTX 0.001 mg) BID BID BID B (OXY 2.5 mg + (OXY 5 mg + (OXY 7.5 mg + (OXY 10 mg + NTX 0.001 mg) NTX 0.001 mg) NTX 0.001 mg) NTX 0.001 mg) QID QID QID QID OXY 2.5 mg QID OXY 5 mg QID OXY 7.5 mg QID OXY 10 mg QID s Placebo OID Placebo OID Placebo OID Placebo OID

0222. The demographics of the four groups was balanced examinations, EKGs, clinical laboratory tests, adverse acroSS the groups as shown in Table 4. events, opioid toxicity assessments and the assessment of opiate withdrawal symptoms using the Short Opiate With TABLE 4 drawal Scale (SOWS) as shown in Table 6 below. Oxycodone Oxycodone Plus Plus TABLE 6 Oxycodone Naltrexone Naltrexone Short Opiate Withdrawal Scale Placebo QID QID BID Please put a check mark in the appropriate box for each of the ITT Population 51 102 104 103 following conditions in the last 24 hours: Female 69% 70% 69% 69% Male 31% 30% 31% 31% Description None Mild Moderate Severe Age 56.O 53.5 53.6 55.1 Feeling Sick Weight (kg) 90.7 93.3 96.O 94.6 Stomach Cramps Muscle Spasms/Twitching Feelings of Coldness 0223 All treatment groups were scheduled for QID dos Heart Pounding Muscular Tension ing to protect the double-blind Study design as shown in Aches and Pains Table 5. Yawning Runny Eyes TABLE 5 Insomnia/Problems Sleeping Treatment QID Daily Dosing Scheme" 0226 Note: This table shows the 10 items of SOWS and Group Upon Waking Noon Afternoon Bedtime the format in which it is administered. A. Oxycodone and Placebo Oxycodone and Placebo Naltrexone Naltrexone 0227. The Study Population was three hundred sixty-two B Oxycodone and Oxycodone Oxycodone and Oxycodone (360) patients with moderate to Severe chronic pain due to Naltrexone and Naltrexone and Osteoarthritis of the hip or knee. According to the Study Naltrexone Naltrexone C Oxycodone Oxycodone Oxycodone Oxycodone design described above, there were to be about 100 patients D Placebo Placebo Placebo Placebo each in the Oxycodone and naltrexone BID, oxycodone and naltrexone QID and oxycodone alone treatment groups, and Doses were to be taken 30-60 minutes before meals and at least 4 hours about 50 patients in the placebo group. apart. On Day 1 (Week 1 only), patients were to receive three doses of study drug (noon, afternoon and bedtime). 0228 Inclusion criteria were as follows: 0224. During the 3-week treatment period, patients 0229 (1) Males and females who were 218 and 270 recorded their PI every 24 hours in their daily diary imme years of age; diately before their bedtime dose. In addition, patients 0230 (2) Females who were postmenopausal, physi recorded adverse events and date/time of taking the Study cally incapable of childbearing, or practicing an accept medication in the daily diary. Patients returned to the clinic able method of birth control. Acceptable methods of on Week 2, Day 1; Week 3, Day 1 and for End of Treatment birth control included Surgical Sterilization, hormonal assessments (tone day) by the investigator. At each clinic contraceptives, or double-barrier methods (condom or Visit, the investigator also collected, additional data, includ diaphragm with a spermicidal agent or IUD). If prac ing quality of analgesia, pain control, the SF-12 Health ticing an acceptable method of birth control, a negative Survey, the WOMAC Osteoarthritis Index and a global urine pregnancy test result was obtained at the Screen assessment of Study medication. Patients were required to ing Visit; return for a post-treatment follow-up visit approximately one week after the final dose of Study medication (two 0231 (3) Patient was ambulatory; days). 0232 (4) Patient had moderate to severe pain in one or 0225 Safety was evaluated by vital signs (blood pres more hip or knee joint(s) caused by Osteoarthritis for at Sure, heart rate, respiratory rate and temperature), physical least three months prior to the Screening Visit; US 2006/0009478 A1 Jan. 12, 2006 28

0233 (5) Patient had moderate to severe pain in the hip 0251 (13) Patient had or is suspected of having para or knee joint(s) while taking one or more oral analgesic lytic ileus, acute abdomen (Serious abdominal pain medication(s) (e.g., NSAIDs, COX-2 inhibitors, trama requiring emergency Surgery), or delayed gastric emp dol, opioid) in the past one month prior to the Screening tying; Visit; 0252 (14) Patient had chronic biliary tract disease, 0234 (6) Patient had a pain intensity score of 25 on an chronic pancreatitis, or inflammatory bowel disorders, 11-point numerical Scale at the Screening Visit; 0253) (15) Patient had untreated myxedema, untreated 0235 (7) Patient had a mean daily diary overall pain hypothyroidism, elevated intracranial preSSure, Severe intensity (taken immediately before their bedtime dose anemia, adrenocortical insufficiency, hypotension or of acetaminophen) of 25 on an 11-point numerical hypovolemia; Scale during the last two days of the 4- to 7-day 0254 (16) Patient had other diseases significant washout period and a confirmatory pain intensity level enough, in the opinion of the Investigator, to pose a risk of 25 on an 11-point numerical Scale measured at the for the administration of study drug or that will inter clinic at Visit 2; fere with pain assessments, 0236 (8) Patient was able to understand and cooperate 0255 (17) Patient had started or stopped monoamine with Study procedures, and has signed a written Oxidase inhibitors, tricyclic antidepressant drugs, Sero informed consent prior to entering the Study; and tonin reuptake inhibitors, glucosamine/chondroitin, or 0237 (9) Patient agreed to refrain from taking any pain St. John's Wort within four weeks prior to receiving medications other than Study drug during the 3-week Study medication. A constant dose for longer than four treatment period. (Aspirin (up to 325 mg/day) was weeks is acceptable; permitted for cardiovascular prophylaxis if at a Stable 0256 (18) Patient was receiving high doses of seda dose one month prior to the Screening Visit.) tives, hypnotics or tranquilizers, 0238 Exclusion criteria for subjects were as follows: 0257 (19) Patient was receiving phenothiazines or 0239 (1) Patient had received a daily opioid dose other agents that compromise vasomotor tone; equivalent (if applicable) of oxycodone >20 mg for two 0258 (20) Patient had a history of alcohol or drug or more days within four weeks prior to the Screening abuse; Visit (as calculated by the Drug Conversion Calculator 0259 (21) Patient had previously received the inves Version 2.0, American Pain Study); tigational Study drug of oxycodone and naltrexone; 0240 (2) Patient had received an opioid within 72 0260 (22) Patient had pparticipated p in another investi hours of the Screening Visit; gational drug trial or therapeutic trial within 30 days of 0241 (3) Patient weighed more than 300 lbs or less the Screening Visit; or than 100 lbs; 0261 (23) Patient had taken analgesic medication 0242 (4) Patient had major surgery within three (other than acetaminophen-up to 5 caplets per day) months prior to the Screening Visit or had Surgery during the 4- to 7-day washout period prior to random planned for this joint during the proposed Study period; ization. 0243 (5) Patient had received oral or parenteral cor 0262 The physical descriptions of the drugs used for the ticosteroid therapy within one month prior to the study were as follows. For the 4-to 7-day washout period, a Screening Visit; container of acetaminophen (500 mg caplets) was dispensed at the Screening Visit in a Sufficient quantity for dosing up 0244 (6) Patient had received an intraarticular injec to five caplets per day. The investigational drug Supplies tion of hyaluronic acid within nine months prior to the were in tablet dosage forms containing oxycodone HCl and Screening Visit; maltrexone HCl, oxycodone HCl or placebo. All of the tablet 0245 (7) Patient had received any epidural or intrath dosage forms were indistinguishable from one another to ecal infusion of any analgesic medication(s) within one facilitate blinding. The tablets were round (approximately 7 month prior to the Screening Visit; mm diameter), biconvex and had a pale yellow color coat ing. The investigational drug Supplies were dispensed in 0246 (8) Patient was pregnant or breast-feeding; these weekly kits. 0247 (9) Patient had a history of severe hepatic or 0263. The study procedures were as follows. Prior to any renal impairment; Study-related activities, written informed consent was signed 0248 (10) Patient had acute hepatitis; and dated by the patient. Clinical examinations were per formed that comprised the Standard-of-care evaluations rou 0249 (11) Patient had a known allergy or significant tinely performed as part of ongoing care for patients with reaction to any of the Study medications, moderate to Severe chronic pain due to Osteoarthritis of the 0250 (12) Patient had severe impairment of pulmo hip or knee. Pain assessments were performed by assessing: nary function, hypercarbia, hypoxia, Significant chronic (1) Pain Intensity, (2) Quality of Analgesia, (3) Pain Control, obstructive airways disease or cor pulmonale, acute or and (4) Global Assessment of Study Medication. Severe bronchial asthma, Sleep apnea Syndrome or 0264. Pain Intensity was assessed by prompting the respiratory depression; patient with the question, “How would you rate your overall US 2006/0009478 A1 Jan. 12, 2006 29 pain intensity at this time?”, and the PI score was recorded patient. The diary issued at Visit 1 was to be used by the in the clinic. Pain Intensity was also assessed by prompting patient to record the following information at bedtime the patient with the question, “How would you rate your immediately before the patient's dose of acetaminophen was overall pain intensity during the past 24 hours?', and a daily taken: (a) overall PI in the past 24 hours, (b) signs and PI diary score was recorded by the patient at bedtime. For Symptoms, and (c) date/time of each acetaminophen dose. both Pain Intensity prompts, the response was Scored on an 0271 The second visit was on the first day of the first 11-point numerical Scale (0=no pain and 10=Severe pain). treatment week of the study. The patients returned to the 0265 Quality of Analgesia was assessed weekly at clinic study center four to seven days after the Screening Visit for visits. The patient was prompted with the question, “How completion of the pre-dose assessments. This visit included would you rate the quality of your pain relief at this time?”, (1) reviewing the take-home diary from the past four to and responses were Selected from poor, fair, good, very Seven days; (2) collecting the bottle of acetaminophen and good, and excellent. performing accountability; (3) a baseline clinic PI rating, (4) reviewing inclusion and exclusion criteria. This assessment 0266 Pain Control was also assessed weekly at clinic also included verifying that (a) the mean daily overall pain Visits. The patient was prompted with the question, “During intensity Score collected in the diary over the last two days the past week, how would you describe your pain control of the 4- to 7-day washout period was 25 (on a scale of 0 during the course of each day'?” Responses were Selected to 10) while off all analgesic medications (except acetami from: Pain was controlled for (1) a few hours or less each nophen as directed); (b) the clinic PI at this visit measured day; (2) Several hours each day; (3) most of each day; and 25 (on a scale of 0 to 10); and (c) checking that the clinical (4) throughout each day. laboratory tests results from the Screening visit were without 0267 Global Assessment of Study Medication was also Significant clinical abnormalities, that the urine pregnancy assessed weekly at clinic Visits. The patient was prompted test was negative (if required), and that the urine drug Screen with the question, “How would you rate the study medica was negative. tion you received this past week? (Please consider the 0272 Patients meeting the study entry criteria were ran quality of your pain relief, your Side effects, your activity domly assigned to one of the four treatment groups, and level, your mood and Sense of well-being, etc. in this were assigned a randomization number and Study medica evaluation.)”. Responses were selected from poor, fair, tion kit number. The following assessments were then con good, Very good, and excellent. ducted: (1) a brief (interim) medical history; (2) vital signs; 0268 Additionally, functional assessments were con (3) blood sample for PKanalysis (procedures for collection, ducted with the SF-12 Health Survey (see Table 1) and the Storage and Shipping of PK Samples were provided under WOMAC Osteoarthritis Index (see Table 2). Separate cover); (4) review and record concomitant medi cations; (5) SF-12 Health Survey; and (6) WOMAC 0269 Safety procedures included vital signs (blood pres Osteoarthritis Index. Sure, respiratory rate, heart rate and temperature), physical examinations, EKGs, clinical laboratory tests, adverse 0273) Once these assessments and procedures were com events, opioid toxicity assessments and the assessment of pleted, the study medication kit was dispensed for Week 1 opiate withdrawal symptoms using the SOWS (see Table 6). (Study Days 1-8). Patients were instructed to take up to three The opioid toxicity assessment included: (A) CNS review by doses of study medication on this day (noon, afternoon and assessing for (1) confusion, altered mental state, (2) exces at bedtime). In addition, patients were instructed to take their Sive drowsiness, lethargy, stupor, (3) Slurred speech (new Day 8 waking dose from this medication kit. The patients onset), (4) respiratory, (5) hypoVentilation, shortness of received their take-home daily diaries and were provided breath, apnea, (6) hypoxia, hypercarbia; and (b) cardiac with an appointment card for the next visit. The Study nurse review by assessing for bradycardia, hypotension, and thoroughly reviewed each section of the diary with the Shock. If patients experienced any of these or other Symp patient. The daily diary issued at Visit 2 was used to record toms that, in the principal investigator's opinion, would pose the following information at Bedtime immediately prior to a significant risk if additional opioid doses were adminis dosing: (1) overall PI in the past 24 hours; (2) Date and time tered, doses were not escalated on Week 2, Day 1 or Week of each dose of study medication taken; and (3) adverse 3, Day 1. eVentS. 0270. At the first visit, pre-enrollment screening was 0274 Patients were contacted by telephone on the eve performed. The following assessments were conducted at nings of Days 3 and 4 of Treatment Week 1. On Day 3, Visit 1, four to seven days prior to enrollment in the study: patients were contacted to determine whether the dose (1) written informed consent, (2) clinic PI, (3) review should be escalated on the morning of Day 4. On Day 4, inclusion and exclusion criteria, (4) detailed medical history patients were contacted to determine whether patients were including concomitant medications taken one month prior to tolerating the higher dose. The telephone visits were also the Screening visit, (5) complete physical examination used to check for adverse events, compliance and concomi including height, weight and Vital signs, (6) EKG (QTc tant medications and to remind the patients to complete the interval only), (7) blood samples for clinical laboratory tests daily diary and bring it to the next visit. (hematology and chemistry), (8) urine sample for clinical laboratory tests, (drug Screening and urinalysis), (9) urine 0275 Patients returned to the study center for their third pregnancy test for all women of childbearing potential, and visit on Week 2, Day 1 (tone day) for the following: (10) dispense acetaminophen, take-home diary and provide 0276 (1) opioid toxicity assessment; an appointment card for the next visit. The Study nurse thoroughly reviewed each section of the diary with the 0277 (2) review take-home diary; US 2006/0009478 A1 Jan. 12, 2006 30

0278 (3) record new/changed adverse events and con events, compliance and concomitant medications, and to comitant medications, remind them to complete the daily diary and bring it to the 0279 (4) collect study medication from Week 1 (Study next visit. Days 1-8) and account for used/unused Supplies; 0305 Patients returned to the study center for their fifth (End of Treatment) visit on Week 3, Day 8 (+one day) for the 0280 (5) vital signs; following: 0281 (6) blood sample for PK analysis; 0306 (1) review take-home diary; (7) quality of analgesia; 0282) 0307 (2) record new/changed adverse events and con 0283) (8) pain control; comitant medications, 0284) (9) global assessment of study medication; 0308 (3) collect study medication from Week 3 (Study 0285) (10) SF-12 Health Survey; Days 1-8) and account for used/unused Supplies; 0309 (4) complete physical examination and vital 0286) (11) WOMAC Osteoarthritis Index; and Signs, 0287 (12) dispense take-home daily diary and study medication kit for Week 2 (Study Days 1-8). 0310 (5) EKG (QTc interval only); 0288 Patients were instructed to take up to three doses of 0311 (5) blood samples for clinical laboratory tests Study medication on this day (noon, afternoon and at bed (hematology and chemistry); time). In addition, patients were instructed to take their Day 8 waking dose from this medication kit. At the conclusion 0312 (6) urine sample for clinical laboratory tests of this visit, the patient was given an appointment card for (urinalysis); the next study visit. 0313 (7) blood sample for PK analysis; 0289 Patients were contacted by telephone on the 0314 (8) quality of analgesia; evening of Day 1 of Treatment Week 2 to determine whether they are tolerating the higher dose; to check for adverse 0315 (9) pain control; events, compliance and concomitant medications, and to remind them to complete the daily diary and bring it to the 0316 (10) global assessment of study medication; next visit. 0317 (11) SF-12 Health Survey; 0290 Patients returned to the study center for their fourth 0318 (12) WOMAC Osteoarthritis Index; visit on Week 3, Day 1 (tone day) for the following: 0319 (13) SOWS; and 0291 (1) opioid toxicity assessment; 0320 (14) dispense take-home daily diary (SOWS and 0292 (2) review take-home diary; adverse event log) for follow-up period. 0293 (3) record new/changed adverse events and con 0321 Blood samples that were taken during the study at comitant medications, various patient Visits were used for a variety of analyses 0294 (4) collect study medication from Week 2 (Study including clinical laboratory tests, PK analysis (see, e.g., Days 1-8) and account for used/unused Supplies; Example 3) and cytokine analysis (see, e.g., Example 4). (5) vital signs; 0322. At the conclusion of this visit, prior to departing the 0295) center, the patient was given an appointment card for the 0296) (6) blood Sample for pk analysis, next Study Visit. Patients were instructed to contact the Study center immediately if they experienced Severe Signs and 0297) (7) quality of analgesia; Symptoms of opioid withdrawal. 0298) (8) pain control; 0323 The study center contacted patients before noon 0299) (9) global assessment of study medication; once daily (for four days after the last dose of study medication) to monitor for Symptoms of opioid withdrawal. 0300 (10) SF-12 Health Survey; On each telephone call, the study center verified that the 0301) (11) WOMAC Osteoarthritis Index; and SOWS have been completed each day (in the morning) by the patients. In addition, there was a check for adverse 0302 (12) dispense take-home daily diary and study events and concomitant medications. If necessary, a clinic medication for Week 3 (Study Days 1-8). Visit was required for those patients with clinically signifi 0303 Patients were instructed to take up to three doses of cant withdrawal Symptoms. Study medication on this day (noon, afternoon and at bed 0324 Patients returned to the study center approximately time). In addition, patients were instructed to take their Day one week (ttwo days) after the last dose of Study medication 8 waking dose from this medication kit. At the conclusion for a post-treatment follow-up visit. At this visit, the fol of this visit, the patient was given an appointment card for lowing assessments were completed: the next study visit. 0304 Patients were contacted by telephone on the 0325 (1) review take-home diary; and evening of Day 1 of Treatment Week 3 to determine whether 0326 (2) record new/changed adverse events and con they are tolerating the higher dose; to check for adverse comitant medications. US 2006/0009478 A1 Jan. 12, 2006

0327 Patients could choose to discontinue study drug or work. Testing employed Type III Sums of Squares. If the Study participation at any time, for any reason, Specified or assumptions of the parametric tests were not valid, non unspecified, and without prejudice. If a patient chose to parametric tests were used. discontinue Study drug early, the investigator requested that the patient return to the clinic within 24 hours of Stopping 0335 For secondary analysis of data, pain intensity the Study medication and complete the end-of-treatment changes, SF-12, and WOMAC were analyzed with the assessments described above, as well as the opioid with ANOVA methods as described above. Within treatment drawal monitoring period described above. The investigator arms, weeks were compared in pairwise fashion using also requested that the patient remain in the Study for the paired-Sample methods. The global assessments, quality of post-treatment follow-up visit. analgesia ratings, and pain control was analyzed at each week, globally and in pairwise fashion, using the Cocharan 0328. For randomization and blinding of the study, the Mantel-Haenszel row mean scores (CMH-RMS) test, using randomization was Stratified on patient Sex, it was not equally spaced Scores. An "observed data” analysis, without Stratified on investigator. The randomization Schedule was any data imputation, was conducted on pain intensity generated using a permuted blockS algorithm. The Study changes, global assessments, quality of analgesia ratings, randomization was unblinded only after all Study patients pain control, SF-12, and WOMAC using the same analysis completed therapy and the database was finalized and methods described previously. locked. 0336 Adverse events reported were mapped to preferred 0329. The primary analysis population for both efficacy terms and organ Systems using the MedDRA mapping and Safety included all patients who took Study medication. System. Adverse events were associated with weeks accord In the event that a patient was randomized incorrectly or was ing to their onset date. The number and percentage of otherwise administered the incorrect Study drug, the patient patients reporting each event were Summarized by treatment was to be analyzed according to the Study drug actually group and week. received. 0337 Treatment groups were examined for differences in 0330 For the efficacy analysis, endpoints were repre the incidence and Severity of Selected opioid-associated Sented and analyzed by week. Missing efficacy data was adverse events, including constipation, dizziness, Somno imputed acroSS weeks using the last-observation-carried lence, headache, pruritus, nausea, vomiting, urinary reten forward (LOCF) method. Thus, the primary procedure for tion, and bradypnoea. The homogeneity of response between the analysis of efficacy data was based on a LOCF approach. males was investigated descriptively. 0331. The daily pain intensity ratings were summarized 0338 Each of the SOWS assessments (Gossop, “The as follows. For each week, the pain intensity recorded on the Development of a Short Opiate Withdrawal Scale (SOWS).” last two full days of dosing within the week, restricted to Addictive Behaviors, Vol. 15, p. 487-490, 1990 (incorpo Day 5 or later, was averaged. If only a single observation rated by reference herein)) on Days 1 through 4 of opioid was available, it was used; otherwise, the endpoint was not withdrawal monitoring was reduced to an average Symptom defined. The pain intensity averages were represented as Score and was Summarized in terms of changes from base both (1) a change from baseline and (2) a percent change line, which was defined as the in-clinic assessment at the end from baseline. The baseline value was defined as the average of treatment visit (Week 3, Day 8). pain intensity over the last two values recorded during the 0339. The study's sensitivity was broadly assessed by baseline period; if necessary, a Single value was used. calculating the power of the Wilcoxon test to detect a 0332 The global assessment, quality of analgesia, and pairwise treatment difference in an underlying normally pain control, recorded at the end of each week, were distributed endpoint where the two treatment group means Summarized in terms of category proportions. differ by one-half a standard deviation. Under these assump tions, the statistical power of a 2-sided Wilcoxon test was: 0333. The SF-12 evaluations, recorded at baseline and at the end of each week, were scored as described in Ware et al., "SF-12: How to score the SF-12 physical and mental health Summary Scales. Quality Metric Inc., Lincoln, R.I., Power of a Pairwise and the Health Assessment Lab, Boston, Mass. (3d Ed. Analyzable Sample Treatment Comparison 1998), which is incorporated by reference herein. The sum Size per Group 0.05-level 0.025-level marization and analysis of the WOMAC Osteoarthritis 1OO 92% 87% Index were specified in the Statistical Analysis Plan per the 90 89% 83% WOMAC User Guide, which is obtainable at the WOMAC 8O 85% 78% organization website www.womac.org/contact/index.cfm 70 80% 72% and incorporated by reference herein. 0334 For primary analysis of data, the primary efficacy endpoint was the percent change from baseline in pain Results were obtained using nGuery Advisor(R), version 4.0 intensity at Week 3. Percent change in pain intensity was (Statistical Solutions Ltd., Boston, Mass.). analyzed using ANOVA methods. The ANOVA model 0340 One efficacy endpoint for this study was percent included factors for treatment, Sex, and their interaction. change in pain intensity from baseline to Week 3. In general, Additional covariates could be added to the model for a dose response relationship was observed. That is, greater exploratory purposes. Pairwise treatment group compari reductions in mean PI occurred as the dose increased in all sons were made using contrasts within the ANOVA frame active treatment groups. The greatest reduction occurred in US 2006/0009478 A1 Jan. 12, 2006 32 the oxycodone plus naltrexone BID combination treatment group. The mean percent change in pain intensity from baseline to Week 3 was 39.2% for this BID group. This was both clinically and Statistically significant when compared to the other treatment groups. Tables 7A, 7B, and 7C show averages for actual values for Pain Intensity at each of Weeks 1, 2 and 3, based on the Intent to Treat Population using the LOCF method and Table 7D shows the baseline values.

TABLE 7A PAIN INTENSITY - BY WEEK ANALYSIS POPULATION: INTENT TO TREAT POPULATION

PLACEBO OXY - NTX QID OXY OID OXY + NTX OID BID TOTAL (N = 50) (N = 102) (N = 102) (N = 102) (N = 356) ACTUAL VALUE AT WEEK 1

N 46 93 96 84 319 MEAN 6.5 6.1 6.3 5.5 6.1 STANDARD DEVATION 2.10 2.17 2.14 2.11 216 MINIMUM 2.5 1.O 1.O O.O O.O MEDIAN 6.5 6.O 6.8 5.5 6.O MAXIMUM 1.O.O 1.O.O 1.O.O 1.O.O 1O.O MODELP-VALUES

TREATMENT O.O53 SEX O.727 TREATMENT - SEX O.860 PAIRWISE COMPARISON P-VALUES

PLACEBOOID 0.225 O.456 O.O13 OXY OID O.561 O.108

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. USING AVERAGE OF LAST TWO DAYS WITHIN EACH DOSING WEEK. 2P-VALUES FROM ANOVA MODEL WITH TREATMENT, SEX, AND TREATMENT + SEX INTERACTIONAS EFFECTS.

0341

TABLE 7B PAIN INTENSITY - BY WEEK1 ANALYSIS POPULATION: INTENT TO TREAT POPULATION

PLACEBO OXY - NTX QID OXY OID OXY + NTX OID BID TOTAL (N = 50) (N = 102) (N = 102) (N = 102) (N = 356) ACTUAL VALUE AT WEEK 2

N 46 93 96 84 319 MEAN 6.2 5.8 6.O 5.0 5.7 STANDARD DEVATION 2.47 2.25 2.20 2.21 2.29 MINIMUM 1.O O.O 1.O O.O O.O MEDIAN 7.0 6.O 6.O 5.0 6.O MAXIMUM 1.O.O 1.O.O 1.O.O 1.O.O 1O.O MODELP-VALUES

TREATMENT O.OO7 SEX 0.972 TREATMENT - SEX 0.795 PAIRWISE COMPARISON P-VALUES2 US 2006/0009478 A1 Jan. 12, 2006 33

TABLE 7B-continued PAIN INTENSITY - BY WEEK ANALYSIS POPULATION: INTENT TO TREAT POPULATION

PLACEBO OXY - NTX QID OXY OID OXY + NTX OID BID TOTAL (N = 50) (N = 102) (N = 102) (N = 102) (N = 356)

PLACEBOOID O.148 O463 O.OO2 OXY OID O.375 O.O46 OXY + NTX OID O.OO)4

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. USING AVERAGE OF LAST TWO DAYS WITHIN EACH DOSING WEEK. 'P-VALUES FROM ANOVA MODEL WITH TREATMENT, SEX, AND TREATMENT + SEX INTERACTIONAS EFFECTS.

0342

TABLE 7C PAIN INTENSITY - BY WEEK1 ANALYSIS POPULATION: INTENT TO TREAT POPULATION

PLACEBO OXY - NTX QID OXY OID OXY + NTX OID BID TOTAL (N = 50) (N = 102) (N = 102) (N = 102) (N = 356) ACTUAL VALUE AT WEEK 3

N 46 93 96 84 319 MEAN 6.1 5.6 5.7 4.5 5.4 STANDARD DEVATION 2.79 2.33 2.43 2.44 2.51 MINIMUM O.O O.O O.O O.O O.O MEDIAN 7.0 5.5 6.O 4.3 5.5 MAXIMUM 1O.O 1.O.O 1.O.O 1.O.O 1O.O MODELP-VALUES

TREATMENT &O.OO1 SEX O416 TREATMENT - SEX O.348 PAIRWISE COMPARISON P-VALUES2

PLACEBOOID O.O92 O.193 &O.OO1 OXY OID O.630 O.OO9 OXY + NTX OID O.OO2

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. USING AVERAGE OF LAST TWO DAYS WITHIN EACH DOSING WEEK. 'P-VALUES FROM ANOVA MODEL WITH TREATMENT, SEX, AND TREATMENT + SEX INTERACTIONAS EFFECTS.

0343)

TABLE 7D PAIN INTENSITY - BY WEEK ANALYSIS POPULATION: INTENT TO TREAT POPULATION

PLACEBO OXY - NTX QID OXY OID OXY + NTX OID BID TOTAL (N = 50) (N = 102) (N = 102) (N = 102) (N = 356) BASELINE US 2006/0009478 A1 Jan. 12, 2006 34

TABLE 7D-continued PAIN INTENSITY - BY WEEK ANALYSIS POPULATION: INTENT TO TREAT POPULATION

PLACEBO OXY - NTX OID OXY OID OXY + NTX OID BID TOTAL (N = 50) (N = 102) (N = 102) (N = 102) (N = 356) N 50 102 1O2 101 355 MEAN 7.7 7.4 7.7 7.6 7.6 STANDARD DEVATION 1.29 1.30 1.41 1.37 1.35 MINIMUM 5.0 5.0 5.0 4.5 4.5 MEDIAN 8.0 7.0 8.0 7.5 7.5 MAXIMUM 1.O.O 1O.O 1.O.O 1O.O 1O.O MODELP-VALUES

TREATMENT O.482 SEX O.O18 TREATMENT - SEX O.876 PAIRWISE COMPARISON P-VALUES2

PLACEBOOID O.22O O.915 O.568 OXY OID O.165 O415 OXY + NTX OID O.S64

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. USING AVERAGE OF LAST TWO DAYS WITHIN EACH DOSING WEEK. 'P-VALUES FROM ANOVA MODEL WITH TREATMENT, SEX, AND TREATMENT + SEX INTERACTIONAS EFFECTS.

0344) Tables 8A, 8B, and 8C for males and 8E, 8F and 8G for females show averages for actual values for Pain Inten sity at Weeks 1, 2 and 3, respectively. Tables 8D and 8H show baseline values for males and females, respectively.

TABLE 8A PAIN INTENSITY - BY WEEK AND SEX ANALYSIS POPULATION: INTENT TO TREAT POPULATION

PLACEBO OXY - NTX QID OXY OID OXY + NTX OID BID TOTAL (N = 15) (N = 31) (N = 32) (N = 32) (N = 110) ACTUAL VALUE AT WEEK 1

N 14 29 29 25 97 MEAN 6.7 5.9 6.1 5.5 6.O STANDARD DEVATION 1.81 2.18 2.07 1.68 1.98 MINIMUM 3.0 1.5 1.O 2.0 1.O MEDIAN 7.3 6.O 6.5 5.5 6.O MAXIMUM 9.O 1.O.O 1.O.O 8.0 1O.O MODELP-VALUES

TREATMENT O.325 PAIRWISE COMPARISON P-VALUES

PLACEBOOID 0.217 O.332 O.069 OXY OID O.741 0.445 OXY + NTX OID O.28O

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. USING AVERAGE OF LAST TWO DAYS WITHIN EACH DOSING WEEK. P-VALUES FROM ANOVA MODEL WITH TREATMENT AS THE EFFECT.

0345) US 2006/0009478 A1 Jan. 12, 2006 35

TABLE 8B PAIN INTENSITY - BY WEEK AND SEX ANALYSIS POPULATION: INTENT TO TREAT POPULATION MALE

PLACEBO OXY - NTX QID OXY OID OXY + NTX OID BID TOTAL (N = 15) (N = 31) (N = 32) (N = 32) (N = 110) ACTUAL VALUE AT WEEK 2

N 14 29 29 25 97 MEAN 6.6 5.5 6.O 4.9 5.7 STANDARD DEVATION 2.04 2.36 2.OO 1.97 216 MINIMUM 3.0 O.O 1.O 1.O O.O MEDIAN 7.3 5.5 6.O 5.0 6.O MAXIMUM 9.O 1O.O 1.O.O 9.O MODELP-VALUES

TREATMENT O.084 PAIRWISE COMPARISON P-VALUES

PLACEBOOID O.117 O.366 O.O17 OXY OID O.404 0.287 OXY + NTX OID O.064

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. USING AVERAGE OF LAST TWO DAYS WITHIN EACH DOSING WEEK. P-VALUES FROM ANOVA MODEL WITH TREATMENT AS THE EFFECT.

0346)

TABLE 8C PAIN INTENSITY - BY WEEK AND SEX ANALYSIS POPULATION: INTENT TO TREAT POPULATION MALE

PLACEBO OXY - NTX QID OXY OID OXY + NTX OID BID TOTAL (N = 15) (N = 31) (N = 32) (N = 32) (N = 110) ACTUAL VALUE AT WEEK 3

N 14 29 29 25 97 MEAN 6.6 5.0 5.6 4.0 5.2 STANDARD DEVATION 2.30 2.45 2.05 2.40 2.42 MINIMUM 2.5 O.O 1.O 0.5 O.O MEDIAN 7.3 4.5 6.O 4.0 5.0 MAXIMUM 9.5 1.O.O 1.O.O 8.5 MODELP-VALUES

TREATMENT O.OO7 PAIRWISE COMPARISON P-VALUES2

PLACEBOOID O.O34 O.149 &O.OO1 OXY OID O.395 O.110 OXY + NTX OID O.O17

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. USING AVERAGE OF LAST TWO DAYS WITHIN EACH DOSING WEEK. P-VALUES FROM ANOVA MODEL WITH TREATMENT AS THE EFFECT.

0347)

TABLE 8D US 2006/0009478 A1 Jan. 12, 2006 36

PAIN INTENSITY - BY WEEK AND SEX ANALYSIS POPULATION: INTENT TO TREAT POPULATION MALE

PLACEBO OXY - NTX QID OXY OID OXY + NTX OID BID TOTAL (N = 15) (N = 31) (N = 32) (N = 32) (N = 110) BASELINE

N 15 33 32 32 110 MEAN 7.4 7.2 7.3 7.3 7.3 STANDARD DEVATION 1.03 1.11 1.35 1.19 1.18 MINIMUM 5.5 5.0 5.0 5.0 5.0 MEDIAN 7.5 7.0 7.5 7.0 7.0 MAXIMUM 9.O 1.O.O 1.O.O 1.O.O 1.O.O MODELP-VALUES

TREATMENT 0.952 PAIRWISE COMPARISON P-VALUES

PLACEBOOID O.583 O.812 O.78O OXY OID O.697 O.736 OXY + NTX OID 0.959

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. USING AVERAGE OF LAST TWO DAYS WITHIN EACH DOSING WEEK. 2P-VALUES FROMANOVA MODEL WITH TREATMENT AS THE EFFECT.

0348

TABLE 8E PAIN INTENSITY - BY WEEK AND SEX ANALYSIS POPULATION: INTENT TO TREAT POPULATION FEMALE

PLACEBO OXY - NTX QID OXY OID OXY + NTX OID BID TOTAL (N = 35) (N = 71) (N = 70) (N = 70) (N = 246) ACTUAL VALUE AT WEEK 1

N 32 64 67 59 222 MEAN 6.4 6.2 6.4 5.5 6.1 STANDARD DEVATION 2.24 2.18 2.18 2.28 2.23 MINIMUM 2.5 1.O 1.O O.O O.O MEDIAN 6.5 6.3 7.0 5.5 6.O MAXIMUM 1.O.O 1.O.O 1.O.O 1.O.O 1O.O MODELP-VALUES

TREATMENT O.081 PAIRWISE COMPARISON P-VALUES

PLACEBOOID O. 649 O.995 0.055 OXY OID O.567 O.O73 OXY + NTX OID O.O18

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. USING AVERAGE OF LAST TWO DAYS WITHIN EACH DOSING WEEK. P-VALUES FROM ANOVA MODEL WITH TREATMENT AS THE EFFECT.

0349)

TABLE 8F PAIN INTENSITY - BY WEEK AND SEX US 2006/0009478 A1 Jan. 12, 2006 37

ANALYSIS POPULATION: INTENT TO TREAT POPULATION FEMALE

PLACEBO OXY - NTX QID OXY OID OXY + NTX OID BID TOTAL (N = 35) (N = 71) (N = 70) (N = 70) (N = 246) ACTUAL VALUE AT WEEK 2

N 32 64 67 59 222 MEAN 6.1 5.9 6.O 5.0 5.7 STANDARD DEVATION 2.64 2.20 2.29 2.32 2.35 MINIMUM 1.O O.O 1.5 O.O O.O MEDIAN 6.5 6.3 6.O 5.0 5.8 MAXIMUM 1.O.O 1.O.O 1.O.O 1.O.O 1O.O MODELP-VALUES

TREATMENT O.052 PAIRWISE COMPARISON P-VALUES2

PLACEBOOID O.699 O.960 O.O39 OXY OID O.676 O.O40 OXY + NTX OID O.O13

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. USING AVERAGE OF LAST TWO DAYS WITHIN EACH DOSING WEEK. P-VALUES FROM ANOVA MODEL WITH TREATMENT AS THE EFFECT.

0350

TABLE 8G PAIN INTENSITY - BY WEEK AND SEX ANALYSIS POPULATION: INTENT TO TREAT POPULATION FEMALE

PLACEBO OXY - NTX QID OXY OID OXY + NTX OID BID TOTAL (N = 35) (N = 71) (N = 70) (N = 70) (N = 246) ACTUAL VALUE AT WEEK 3

N 32 64 67 59 222 MEAN 5.9 5.9 5.7 4.8 5.5 STANDARD DEVATION 2.98 2.25 2.59 2.44 2.54 MINIMUM O.O O.O O.O O.O O.O MEDIAN 6.O 6.O 6.O 5.0 5.5 MAXIMUM 1.O.O 1.O.O 1.O.O 1.O.O 1O.O MODELP-VALUES

TREATMENT 0.057 PAIRWISE COMPARISON P-VALUES2

PLACEBOOID O.977 O.769 O.O44 OXY OID O.744 O.O16 OXY + NTX OID O.O34

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. USING AVERAGE OF LAST TWO DAYS WITHIN EACH DOSING WEEK. 2P-VALUES FROMANOVA MODEL WITH TREATMENT AS THE EFFECT.

0351)

TABLE 8H PAIN INTENSITY - BY WEEK AND SEX ANALYSIS POPULATION: INTENT TO TREAT POPULATION FEMALE US 2006/0009478 A1 Jan. 12, 2006 38

PLACEBO OXY - NTX QID OXY OID OXY + NTX OID BID TOTAL (N = 35) (N = 71) (N = 70) (N = 70) (N = 246) BASELINE

N 35 71 70 69 245 MEAN 7.9 7.4 7.9 7.7 7.7 STANDARD DEVATION 1.38 1.38 1.41 1.43 1.41 MINIMUM 5.0 5.0 5.0 4.5 4.5 MEDIAN 8.0 7.5 8.0 7.5 8.0 MAXIMUM 1.O.O 1.O.O 1.O.O 1.O.O 1O.O MODELP-VALUES

TREATMENT O.248 PAIRWISE COMPARISON P-VALUES PLACEBOOID 0.155 O.902 O.S30 OXY OID O.O58 O.332 OXY + NTX OID O.358

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. USING AVERAGE OF LAST TWO DAYS WITHIN EACH DOSING WEEK. 2P-VALUES FROMANOVA MODEL WITH TREATMENT AS THE EFFECT.

0352 Tables 9A, 9B and 9C show the percent change from baseline PI scores at Weeks 1, 2 and 3, respectively.

TABLE 9A PAIN INTENSITY - BY WEEK1 ANALYSIS POPULATION: INTENT TO TREAT POPULATION

PLACEBO OXY - NTX QID OXY OID OXY + NTX OID BID TOTAL (N = 50) (N = 102) (N = 102) (N = 102) (N = 356) PERCENT CHANGE FROM BASELINE TO WEEK 1

N 46 93 96 83 31.8 MEAN -16.6 -18.4 -17.8 -26.7 -20.1 STANDARD DEVATION 21.86 25.09 26.27 25.8O 25.40 MINIMUM -75.O -83.3 -83.3 -100.0 -100.0 MEDIAN -12.9 -16.7 -15.5 -25.0 -17.6 MAXIMUM 33.3 SO.O 66.7 16.7 66.7 MODELP-VALUES

TREATMENT O.142 SEX O.224 TREATMENT - SEX O.751 PAIRWISE COMPARISON P-VALUES2

PLACEBOOID O496 O612 OXY OID O.827 OXY + NTX OID

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. USING AVERAGE OF LAST TWO DAYS WITHIN EACH DOSING WEEK. 'P-VALUES FROM ANOVA MODEL WITH TREATMENT, SEX, AND TREATMENT + SEX INTERACTION AS EFFECTS.

0353)

TABLE 9B

PAIN INTENSITY - BY WEEK ANALYSIS POPULATION: INTENT TO TREAT POPULATION US 2006/0009478 A1 Jan. 12, 2006 39

PLACEBO OXY - NTX QID OXY OID OXY + NTX OID BID TOTAL (N = 50) (N = 102) (N = 102) (N = 102) (N = 356) PERCENT CHANGE FROM BASELINE TO WEEK 2

N 46 93 96 83 31.8 MEAN -20.4 -22.9 -21.2 -33.9 -24.9 STANDARD DEVATION 28.55 27.52 28.17 27.24 28.19 MINIMUM -84.6 -100.0 -83.3 -100.0 -100.0 MEDIAN -13.8 -20.0 -20.0 -33.3 -21.4 MAXIMUM 58.3 42.9 66.7 12.5 66.7 MODELP-VALUES

TREATMENT O.O13 SEX O.232 TREATMENT - SEX O622 PAIRWISE COMPARISON P-VALUES2

PLACEBOOID O341 O.718 O.OO7 OXY OID O462 O.O31 OXY + NTX OID O.OO)4

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. USING AVERAGE OF LAST TWO DAYS WITHIN EACH DOSING WEEK. 'P-VALUES FROM ANOVA MODEL WITH TREATMENT, SEX, AND TREATMENT + SEX INTERACTION AS EFFECTS.

0354) and oxycodone plus naltrexone BID were significantly better

TABLE 9C PAIN INTENSITY - BY WEEK ANALYSIS POPULATION: INTENT TO TREAT POPULATION

PLACEBO OXY - NTX QID OXY OID OXY + NTX OID BID TOTAL (N = 50) (N = 102) (N = 102) (N = 102) (N = 356) PERCENT CHANGE FROM BASELINE TO WEEK 3

N 46 93 96 83 31.8 MEAN -21.5 -24.6 -26.0 -39.2 -28.4 STANDARD DEVATION 3166 29.22 31.16 32.51 31.89 MINIMUM -1OO.O -100.0 -100.0 -100.0 -100.0 MEDIAN -17.6 -20.0 -23.5 -40.0 -25.0 MAXIMUM 58.3 42.9 66.7 55.6 66.7 MODELP-VALUES

TREATMENT O.OO2 SEX 0.855 TREATMENT - SEX O.221 PAIRWISE COMPARISON P-VALUES2

PLACEBOOID O.219 O.282 &O.OO1 OXY OID O848 O.OO6 OXY + NTX OID O.OO3

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. USING AVERAGE OF LAST TWO DAYS WITHIN EACH DOSING WEEK. 'P-VALUES FROM ANOVA MODEL WITH TREATMENT, SEX, AND TREATMENT + SEX INTERACTION AS EFFECTS.

0355 Another efficacy endpoint for this study was than placebo as shown in Table 10C. A quality of analgesia assessments of quality of analgesia and the results are shown assessment at Week 3 of very good or excellent was reported in Tables 10A, 10B and 10C. for Weeks 1, 2 and 3, by 12.0% of patients treated with placebo, 19.6% of patients respectively. The oxycodone plus naltrexone BID treatment treated with oxycodone alone QID, 10.6% of patients with group Show a consistent and greater improvement in the oxycodone plus naltrexone QID, and 33.3% of patients quality of analgesia at each of Weeks 1 and 2 (see Tables treated with oxycodone plus naltrexone BID. 10A and 10B). At Week 3, oxycodone plus naltrexone QID US 2006/0009478 A1 Jan. 12, 2006 40

TABLE 10A

OUALITY OF ANALGESIA - BY WEEK ANALYSIS POPULATION: INTENT TO TREAT POPULATION

PLACEBOOID OXY OID OXY + NTX OID OXY + NTX BID TOTAL (N = 50) (N = 102) (N = 102) (N = 102) (N = 356) WEEK 1 EXCELLENT (4) 1 (2.0%) 3 (2.9%) 3 (2.9%) 3 (2.9%) 10 (2.8%) VERY GOOD (3) 5 (10.0%) 8 (7.8%) 13 (12.7%) 14 (13.7%) 40 (11.2%) GOOD (2) 13 (26.0%) 18 (37.3%) 26 (25.5%) 29 (28.4%) 106 (29.8%) FAIR (1) 13 (26.0%) 31 (30.4%) 33 (32.4%) 34 (33.3%) 111 (31.2%) POOR (O) 17 (34.0%) 18 (17.6%) 25 (24.5%) 21 (20.6%) 81 (22.8%) MISSING 1 (2.0%) 4 (3.9%) 2 (2.0%) 1 (1.0%) 8 (2.2%) OVERALL P-VALUE O446 PAIRWISE COMPARISON P-VALUES

PLACEBOOID O.125 O.353 O.162 OXY OID O.5O1 0.925 OXY + NTX OID 0.572

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. COCHRAN-MANTEL-HAENSZEL (ROW MEAN SCORES) TEST ACROSS TREATMENT GROUPS USING EQUALLY SPACED SCORES. 2COCHRAN-MANTEL-HAENSZEL (ROW MEAN SCORES) TEST BETWEEN TREATMENT GROUPS USING EQUALLY SPACED SCORES.

0356)

TABLE 1 OB

OUALITY OF ANALGESIA - BY WEEK ANALYSIS POPULATION: INTENT TO TREAT POPULATION

PLACEBOOID OXY OID OXY + NTX OID OXY + NTX BID TOTAL (N = 50) (N = 102) (N = 102) (N = 102) (N = 356) WEEK 2 EXCELLENT (4) 2 (4.0%) 4 (3.9%) 4 (3.9%) 6 (5.9%) 16 (4.5%) VERY GOOD (3) 8 (16.0%) 16 (15.7%) 13 (12.7%) 28 (27.5%) 65 (18.3%) GOOD (2) 15 (30.0%) 30 (29.4%) 37 (36.3%) 21 (20.6%) 103 (28.9%) FAIR (1) 6 (12.0%) 29 (28.4%) 24 (23.5%) 28 (27.5%) 87 (24.4%) POOR (O) 18 (36.0%) 19 (18.6%) 22 (21.6%) 18 (17.6%) 77 (21.6%) MISSING 1 (2.0%) 4 (3.9%) 2 (2.0%) 1 (1.0%) 8 (2.2%) OVERALL P-VALUE O.254 PAIRWISE COMPARISON P-VALUES2

PLACEBOOID O.391 O.478 O.O81 OXY OID O.841 O.221 OXY + NTX OID 0.155

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. COCHRAN-MANTEL-HAENSZEL (ROW MEAN SCORES) TEST ACROSS TREATMENT GROUPS USING EQUALLY SPACED SCORES. °COCHRAN-MANTEL-HAENSZEL (ROW MEAN SCORES) TEST BETWEEN TREATMENT GROUPS USING EQUALLY SPACED SCORES.

0357)

TABLE 10C

OUALITY OF ANALGESIA - BY WEEK ANALYSIS POPULATION: INTENT TO TREAT POPULATION US 2006/0009478 A1 Jan. 12, 2006 41

PLACEBOOID OXY OID OXY + NTX OID OXY + NTX BID TOTAL (N = 50) (N = 102) (N = 102) (N = 102) (N = 356) WEEK 3 EXCELLENT (4) 0 (0.0%) 5 (4.9%) 3 (2.9%) 8 (7.8%) 16 (4.5%) VERY GOOD (3) 6 (12.0%) 15 (14.7%) 17 (16.7%) 26 (25.5%) 64 (18.0%) GOOD (2) 14 (28.0%) 32 (31.4%) 34 (33.3%) 22 (21.6%) 102 (28.7%) FAIR (1) 11 (22.0%) 23 (22.5%) 27 (26.5%) 28 (27.5%) 89 (25.0%) POOR (O) 18 (36.0%) 23 (22.5%) 19 (18.6%) 17 (16.7%) 77 (21.6%) MISSING 1 (2.0%) 4 (3.9%) 2 (2.0%) 1 (1.0%) 8 (2.2%) OVERALL P-VALUE' O.O17 PAIRWISE COMPARISON P-VALUES

PLACEBOOID O.O52 O.O28 O.OO2 OXY OID 0.855 O.139 OXY + NTX OID O.173

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. COCHRAN-MANTEL-HAENSZEL (ROW MEAN SCORES) TEST ACROSS TREATMENT GROUPS USING EQUALLY SPACED SCORES. 2COCHRAN-MANTEL-HAENSZEL (ROW MEAN SCORES) TEST BETWEEN TREATMENT GROUPS USING EQUALLY SPACED SCORES.

0358 Another efficacy endpoint for this study was a assessment for WeekS 1, 2 and 3, respectively, which were global assessment and the results are shown in Tables 11A, determined using the Cochran-Mantel-Haenszel row mean 11B and 11C for Weeks 1, 2 and 3, respectively. At Week 3, scores (CMH-RMS) test, using equally spaced scores. Thus, Oxycodone plus naltrexone QID and oxycodone plus naltr the results in Table 11C generally show a population shift exone BID were statistically significantly better than pla from patient responses of poor and fair toward patient cebo (in pairwise comparisons) as shown in Table 11C. A responses of Very good and excellent when comparing the global assessment of Very good or excellent at Week 3 was placebo group to the oxycodone alone QID, oxycodone plus reported by 16.0% of patients treated with oxycodone plus maltrexone QID and oxycodone plus naltrexone BID treat maltrexone QID, 19.6% of patients treated with oxycodone ment groups. Larger percentages of patients in the oxyc alone QID, 22.5% of patients with oxycodone plus naltrex odone plus naltrexone BID treatment group gave responses one QID, and 30.4% of patients treated with oxycodone plus of Very good or excellent. maltrexone BID. Tables 11A, 11B and 11C also show the p

TABLE 11A

GLOBAL ASSESSMENT - BY WEEK ANALYSIS POPULATION: INTENT TO TREAT POPULATION

PLACEBOOD OXY OID OXY + NTX OID OXY + NTXBID TOTAL (N = 50) (N = 102) (N = 102) (N = 102) (N = 356) WEEK 1 EXCELLENT (4) 0 (0.0%) 3 (2.9%) 5 (4.9%) 2 (2.0%) 10 (2.8%) VERY GOOD (3) 8 (16.0%) 12 (11.8%) 17 (16.7%) 18 (17.6%) 55 (15.4%) GOOD (2) 11 (22.0%) 30 (29.4%) 27 (26.5%) 31 (30.4%) 99 (27.8%) FAIR (1) 14 (28.0%) 37 (36.3%) 25 (24.5%) 26 (25.5%) 102 (28.7%) POOR (O) 16 (32.0%) 16 (15.7%) 26 (25.5%) 24 (23.5%) 82 (23.0%) MISSING 1 (2.0%) 4 (3.9%) 2 (2.0%) 1 (1.0%) 8 (2.2%) OVERALL P-VALUE' O.487 PAIRWISE COMPARISON P-VALUES

PLACEBOOID O-160 O.174 O.173 OXY OID O.896 0.970 OXY + NTX OID 0.927

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. COCHRAN-MANTEL-HAENSZEL (ROW MEAN SCORES) TEST ACROSS TREATMENT GROUPS USING EQUALLY SPACED SCORES. 2COCHRAN-MANTEL-HAENSZEL (ROW MEAN SCORES) TEST BETWEEN TREATMENT GROUPS USING EQUALLY SPACED SCORES. value VS. placebo calculated for the Scores from the global 0359

TABLE 11B US 2006/0009478 A1 Jan. 12, 2006 42

GLOBAL ASSESSMENT - BY WEEK ANALYSIS POPULATION: INTENT TO TREAT POPULATION

PLACEBOOID OXY OID OXY + NTX OID OXY + NTX BID TOTAL (N = 50) (N = 102) (N = 102) (N = 102) (N = 356) WEEK 2 EXCELLENT (4) 0 (0.0%) 6 (5.9%) 4 (3.9%) 6 (5.9%) 16 (4.5%) VERY GOOD (3) 10 (20.0%) 14 (33.7%) 14 (13.7%) 20 (19.6%) 58 (16.3%) GOOD (2) 13 (26.0%) 13 (32.4%) 38 (37.3%) 28 (27.5%) 112 (31.5%) FAIR (1) 7 (14.0%) 29 (28.4%) 22 (21.6%) 23 (22.5%) 81 (22.8%) POOR (O) 19 (38.0%) 16 (15.7%) 22 (21.6%) 24 (23.5%) 81 (22.8%) MISSING 1 (2.0%) 4 (3.9%) 2 (2.0%) 1 (1.0%) 9 (2.2%) OVERALL P-VALUE' O.319 PAIRWISE COMPARISON P-VALUES

PLACEBOOID O.166 O.12O OXY OID 0.597 O.860 OXY + NTX OID O.742

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. COCHRAN-MANTEL-HAENSZEL (ROW MEAN SCORES) TEST ACROSS TREATMENT GROUPS USING EQUALLY SPACED SCORES. 2COCHRAN-MANTEL-HAENSZEL (ROW MEAN SCORES) TEST BETWEEN TREATMENT GROUPS USING EQUALLY SPACED SCORES.

0360) from Week 1 to Week 3. As shown in Tables 12A, 12B and

TABLE 11C

GLOBAL ASSESSMENT - BY WEEK ANALYSIS POPULATION: INTENT TO TREAT POPULATION

PLACEBOOID OXY OID OXY + NTX OID OXY + NTX BID TOTAL (N = 50) (N = 102) (N = 102) (N = 102) (N = 356) WEEK 3 EXCELLENT (4) 1 (2.0%) 6 (5.9%) 5 (4.9%) 9 (8.8%) 21 (5.9%) VERY GOOD (3) 7 (14.0%) 14 (13.7%) 18 (17.6%) 22 (21.6%) 61 (17.1%) GOOD (2) 13 (26.0%) 36 (35.3%) 34 (33.3%) 23 (22.5%) 106 (29.8%) FAIR (1) 9 (18.0%) 18 (17.6%) 21 (20.6%) 22 (21.6%) 70 (19.7%) POOR (O) 19 (38.0%) 24 (23.5%) 22 (21.6%) 25 (24.5%) 90 (25.3%) MISSING 1 (2.0%) 4 (3.9%) 2 (2.0%) 1 (1.0%) 8 (2.2%) OVERALL P-VALUE O.165 PAIRWISE COMPARISON P-VALUES

PLACEBOOID O.O78 O.O48 O.O39 OXY OID O.818 O604 OXY + NTX OID O.760

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. COCHRAN-MANTEL-HAENSZEL (ROW MEAN SCORES) TEST ACROSS TREATMENT GROUPS USING EQUALLY SPACED SCORES. 2COCHRAN-MANTEL-HAENSZEL (ROW MEAN SCORES) TEST BETWEEN TREATMENT GROUPS USING EQUALLY SPACED SCORES.

0361) Another efficacy endpoint for this study was an 12C, patients in the Oxycodone plus naltrexone BID treat assessment of pain control and the results are shown in ment group showed improved pain control when compared Tables 12A, 12B and 12C for Weeks 1, 2 and 3, respectively. to placebo at each week of treatment. Tables 12A, 12B and From Week 1 to Weeks 2 and 3, there were significant changes within treatment group (indicating better control 12C also show the p value vs. placebo calculated for the throughout the day) in the pain control assessments for the scores from Pain Control, which were determined using the Oxycodone plus naltrexone BID treatment group. There Cochran-Mantel-Haenszel row mean scores (CMH-RMS) were also Statistically significant changes for oxycodone test, using equally Spaced Scores. plus naltrexone QID from Week 1 to Week 3 and for placebo

TABLE 12A US 2006/0009478 A1 Jan. 12, 2006 43

PAIN CONTROL - BY WEEK ANALYSIS POPULATION: INTENT TO TREAT POPULATION

PLACEBO OXY - NTX OXY - NTX QID OXY OID QID BID TOTAL (N = 50) (N = 102) (N = 102) (N = 102) (N = 356) WEEK 1 PAIN CONTROLLED THROUGHOUT EACH DAY (4) 2 (4.0%) 10 (9.8%) 5 (4.9%) 5 (4.9%) 22 (6.2%) PAIN CONTROLLED MOST OF EACH DAY (3) 8 (16.0%) 17 (16.7%) 20 (19.6%) 23 (22.5%) 68 (19.1%) PAIN CONTROLLED SEVERAL HRS EACH DAY (2) 8 (16.0%) 29 (28.4%) 31 (30.4%) 29 (28.4%) 97 (27.2%) PAIN CONTROLLED A FEW HRS/LESS EACH DAY (1) 31 (62.0%) 42 (41.2%) 44 (43.1%) 44 (43.1%) 161 (45.2%) MISSING 1 (2.0%) 4 (3.9%) 2 (2.0%) 1 (1.0%) 8 (2.2%) OVERALL P-VALUE 0.227 PAIRWISE COMPARISON P-VALUES

PLACEBOOID O.O51 O.120 O.084 OXY OID O.514 O.673 OXY + NTX OID O810

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. COCHRAN-MANTEL-HAENSZEL (ROW MEAN SCORES) TEST ACROSS TREATMENT GROUPS USING EQUALLY SPACED SCORES. 2COCHRAN-MANTEL-HAENSZEL (ROW MEAN SCORES) TEST BETWEEN TREATMENT GROUPS USING EQUALLY SPACED SCORES.

0362

TABLE 12B

PAIN CONTROL - BY WEEK ANALYSIS POPULATION: INTENT TO TREAT POPULATION

PLACEBO OXY - NTX OXY - NTX QID OXY OID QID BID TOTAL (N = 50) (N = 102) (N = 102) (N = 102) (N = 356) WEEK 2 PAIN CONTROLLED THROUGHOUT EACH DAY (4) 2 (4.0%) 10 (9.8%) 6 (5.9%) 9 (8.8%) 27 (7.6%) PAIN CONTROLLED MOST OF EACH DAY (3) 11 (22.0%) 26 (25.5%) 29 (28.4%) 33 (32.4%) 99 (27.8%) PAIN CONTROLLED SEVERAL HRS EACH DAY (2) 11 (22.0%) 26 (25.5%) 26 (25.5%) 18 (17.6%) 81 (22.8%) PAIN CONTROLLED A FEW HRS/LESS EACH DAY (1) 25 (50.0%) 36 (35.3%) 39 (38.2%) 41 (40.2%) 141 (39.6%) MISSING 1 (2.0%) 4 (3.9%) 2 (2.0%) 1 (1.0%) 8 (2.2%) OVERALL P-VALUE O.299 PAIRWISE COMPARISON P-VALUES2

PLACEBOOID O.08O 0.179 O.O87 OXY OID O.S60 O.983 OXY + NTX OID O.577

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. COCHRAN-MANTEL-HAENSZEL (ROW MEAN SCORES) TEST ACROSS TREATMENT GROUPS USING EQUALLY SPACED SCORES. °COCHRAN-MANTEL-HAENSZEL (ROW MEAN SCORES) TEST BETWEEN TREATMENT GROUPS USING EQUALLY SPACED SCORES.

0363) US 2006/0009478 A1 Jan. 12, 2006 44

TABLE 12C

PAIN CONTROL - BY WEEK ANALYSIS POPULATION: INTENT TO TREAT POPULATION

PLACEBO OXY - NTX OXY - NTX QID OXY OID QID BID TOTAL (N = 50) (N = 102) (N = 102) (N = 102) (N = 356) WEEK 3 PAIN CONTROLLED THROUGHOUT EACH DAY (4) 3 (6.0%) 8 (7.8%) 7 (6.9%) 12 (21.8%) 30 (8.4%) PAIN CONTROLLED MOST OF EACH DAY (3) 10 (20.0%) 27 (26.5%) 31 (30.4%) 32 (31.4%) 100 (28.1%) PAIN CONTROLLED SEVERAL HRS EACH DAY (2) 11 (22.0%) 28 (27.5%) 22 (21.6%) 16 (17.6%) 79 (22.2%) PAIN CONTROLLED A FEW HRS/LESS EACH DAY (1) 25 (50.0%) 35 (34.3%) 40 (39.2%) 39 (38.2%) 139 (39.0%) MISSING 1 (2.0%) 4 (3.9%) 2 (2.0%) 1 (1.0%) 8 (2.2%) OVERALL P-VALUE O.259 PAIRWISE COMPARISON P-VALUES

PLACEBOOID O.123 O.177 0.055 OXY OID O822 0.553 OXY + NTX OID O419

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. COCHRAN-MANTEL-HAENSZEL (ROW MEAN SCORES) TEST ACROSS TREATMENT GROUPS USING EQUALLY SPACED SCORES. 2COCHRAN-MANTEL-HAENSZEL (ROW MEAN SCORES) TEST BETWEEN TREATMENT GROUPS USING EQUALLY SPACED SCORES.

0364) Another efficacy endpoint for this study was a than placebo at Weeks 2 and 3 as measured by the WOMAC functional assessment using WOMAC, including its three pain SubScale, StiffneSS SubScale, physical function SubScale Subscales for pain, Stiffness and physical function. The and total score, as shown below in Tables 13A, 13B and 13C actual values from the WOMAC pain subscale are shown in (pain), 14A, 14B and 14C (stiffness), 15A, 15B and 15C Tables 13A, 13B and 13C for Weeks 1, 2 and 3, respectively (physical function) and 16A, 16B and 16C (total score). In and Table 13D shows the baseline values. Greater improve each case, the A, B and C tables show the values at Weeks ments (% change from baseline to Week 3) were observed 1, 2 and 3, respectively and the D tables show the baseline with BID administration of oxycodone plus naltrexone in all values.

TABLE 13A

WOMAC OSTEOARTHRITIS PAIN SUBSCALE - BY WEEK ANALYSIS POPULATION: INTENT TO TREAT POPULATION

PLACEBO OXY - NTX OID OXY OID OXY + NTX OID BID TOTAL (N = 50) (N = 102) (N = 102) (N = 102) (N = 356) ACTUAL VALUE AT WEEK 1

50 98 1OO 1OO 348 MEAN 3.11.1 263.2 292.5 2719 281.0 STANDARD DEVATION 121.29 124.90 107.04 119.53 118.60 MINIMUM 37.O 3.0 28.0 O.O O.O MEDIAN 32O.O 279.0 312.O 274.O 297.0 MAXIMUM SOO.O 483.0 492.0 4.88.0 SOO.O MODELP-VALUES

TREATMENT 0.079 SEX O.38O TREATMENT - SEX O.856 PAIRWISE COMPARISON P-VALUES

PLACEBOOID O.O29 O.531 O.088 OXY OID O.O53 0.544 OXY + NTX OID 0.179

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. "P-VALUES FROM ANOVA MODEL WITH TREATMENT, SEX, AND TREATMENT + SEX INTERACTIONAS EFFECTS. categories (pain, stiffness, or physical function). Oxycodone plus naltrexone BID was statistically significantly better 0365) US 2006/0009478 A1 Jan. 12, 2006 45

TABLE 13B

WOMAC OSTEOARTHRITIS PAIN SUBSCALE - BY WEEK ANALYSIS POPULATION: INTENT TO TREAT POPULATION

PLACEBO OXY - NTX QID OXY OID OXY + NTX OID BID TOTAL (N = 50) (N = 102) (N = 102) (N = 102) (N = 356) ACTUAL VALUE AT WEEK 2

N 50 98 1OO 101 349 MEAN 285.7 245.O 257.2 237.7 252.2 STANDARD DEVATION 144.01 131.13 120.08 133.58 131.10 MINIMUM 14.O O.O 22.O O.O O.O MEDIAN 295.5 227.5 272.O 226.O 257.5 MAXIMUM SOO.O 482.O 492.0 494.O SOO.O MODELP-VALUES

TREATMENT O.107 SEX 0.559 TREATMENT - SEX O631 PAIRWISE COMPARISON P-VALUES

PLACEBOOID O.064 O.23O O.O2O OXY OID O.415 O.568 OXY + NTX OID O161

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. 'P-VALUES FROM ANOVA MODEL WITH TREATMENT, SEX, AND TREATMENT + SEX INTERACTIONAS EFFECTS.

0366)

TABLE 13C

WOMAC OSTEOARTHRITIS PAIN SUBSCALE - BY WEEK ANALYSIS POPULATION: INTENT TO TREAT POPULATION

PLACEBO OXY - NTX QID OXY OID OXY + NTX OID BID TOTAL (N = 50) (N = 102) (N = 102) (N = 102) (N = 356) ACTUAL VALUE AT WEEK 3

N 50 98 1OO 101 349 MEAN 269.1 238.7 245.3 225.7 241.2 STANDARD DEVATION 160.58 135.11 131.06 139.11 139.12 MINIMUM 4.0 O.O O.O O.O O.O MEDIAN 316.5 225.0 28O.O 211.O 244.O MAXIMUM SOO.O 488.O 492.0 495.0 SOO.O MODELP-VALUES

TREATMENT 0.172 SEX 0.155 TREATMENT - SEX O.439 PAIRWISE COMPARISON P-VALUES

PLACEBOOID O.154 O.354 O.O35 OXY OID O.531 O.409 OXY + NTX OID O.142

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. 'P-VALUES FROM ANOVA MODEL WITH TREATMENT, SEX, AND TREATMENT + SEX INTERACTIONAS EFFECTS.

0367) US 2006/0009478 A1 Jan. 12, 2006 46

TABLE 13D

WOMAC OSTEOARTHRITIS PAIN SUBSCALE - BY WEEK ANALYSIS POPULATION: INTENT TO TREAT POPULATION

PLACEBO OXY - NTX QID OXY OID OXY + NTX OID BID TOTAL (N = 50) (N = 102) (N = 102) (N = 102) (N = 356) BASELINE

N 50 102 1O2 101 355 MEAN 355.1 327.9 342.9 342.7 340.3 STANDARD DEVATION 80.68 90.62 71.40 80.97 81.56 MINIMUM 134.O 25.0 148.0 86.0 25.0 MEDIAN 363.5 338.0 340.O 35O.O 347.O MAXIMUM 489.O SOO.O 482.O 490.0 SOO.O MODELP-VALUES

TREATMENT O.371 SEX O.O21 TREATMENT - SEX 0.925 PAIRWISE COMPARISON P-VALUES

PLACEBOOID O.110 O.586 O481 OXY OID O.190 O.267 OXY + NTX OID O.842

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. 'P-VALUES FROM ANOVA MODEL WITH TREATMENT, SEX, AND TREATMENT + SEX INTERACTIONAS EFFECTS.

0368)

TABLE 14A

WOMAC OSTEOARTHRITIS STIFFNESS SUBSCALE - BY WEEK ANALYSIS POPULATION: INTENT TO TREAT POPULATION

PLACEBO OXY - NTX QID OXY OID OXY + NTX OID BID TOTAL (N = 50) (N = 102) (N = 102) (N = 102) (N = 356) ACTUAL VALUE AT WEEK 1

N 49 98 1OO 99 346 MEAN 131.0 120.3 127.4 119.O 123.5 STANDARD DEVATION SO41 51.28 44.29 51.32 49.24 MINIMUM 8.0 2.O 6.O O.O O.O MEDIAN 139.O 129.5 131.0 128.0 130.5 MAXIMUM 1990 2OO.O 1970 2OO.O 2OO.O MODELP-VALUES

TREATMENT O.274 SEX O.290 TREATMENT - SEX O.656 PAIRWISE COMPARISON P-VALUES

PLACEBOOID O.192 O.858 O.174 OXY OID O.163 O.954 OXY + NTX OID O.142

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. 'P-VALUES FROM ANOVA MODEL WITH TREATMENT, SEX, AND TREATMENT + SEX INTERACTIONAS EFFECTS.

0369) US 2006/0009478 A1 Jan. 12, 2006 47

TABLE 1.4B

WOMAC OSTEOARTHRITIS STIFFNESS SUBSCALE - BY WEEK ANALYSIS POPULATION: INTENT TO TREAT POPULATION

PLACEBO OXY - NTX QID OXY OID OXY + NTX OID BID TOTAL (N = 50) (N = 102) (N = 102) (N = 102) (N = 356) ACTUAL VALUE AT WEEK 2

N 50 98 1OO 1OO 348 MEAN 128.3 111.4 115.8 106.5 113.7 STANDARD DEVATION 55.95 56.29 48.60 55.44 54.10 MINIMUM 8.0 O.O 8.0 O.O O.O MEDIAN 142.5 119.5 125.0 113.5 121.0 MAXIMUM 2OO.O 1990 1970 2OO.O 2OO.O MODELP-VALUES

TREATMENT O.O98 SEX O.249 TREATMENT - SEX 0.745 PAIRWISE COMPARISON P-VALUES

PLACEBOOID O.O61 O.238 O.O19 OXY OID O.383 O.569 OXY + NTX OID O.145

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. 'P-VALUES FROM ANOVA MODEL WITH TREATMENT, SEX, AND TREATMENT + SEX INTERACTIONAS EFFECTS.

0370

TABLE 14C

WOMAC OSTEOARTHRITIS STIFFNESS SUBSCALE - BY WEEK ANALYSIS POPULATION: INTENT TO TREAT POPULATION

PLACEBO OXY - NTX QID OXY OID OXY + NTX OID BID TOTAL (N = 50) (N = 102) (N = 102) (N = 102) (N = 356) ACTUAL VALUE AT WEEK 3

N 50 98 1OO 1OO 348 MEAN 119.8 106.3 110.7 101.1 208.O STANDARD DEVATION 64.12 57.99 53.42 57.66 57.62 MINIMUM 4.0 O.O O.O O.O O.O MEDIAN 139.5 109.O 117.5 113.5 117.5 MAXIMUM 2OO.O 2OO.O 1970 2OO.O 2OO.O MODELP-VALUES

TREATMENT O.148 SEX O.O68 TREATMENT - SEX O396 PAIRWISE COMPARISON P-VALUES

PLACEBOOID O.143 O.496 O.042 OXY OID O.328 O491 OXY + NTX OID O.O92

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. 'P-VALUES FROM ANOVA MODEL WITH TREATMENT, SEX, AND TREATMENT + SEX INTERACTIONAS EFFECTS.

0371) US 2006/0009478 A1 Jan. 12, 2006 48

TABLE 1.4D

WOMAC OSTEOARTHRITIS STIFFNESS SUBSCALE - BY WEEK ANALYSIS POPULATION: INTENT TO TREAT POPULATION

PLACEBO OXY - NTX QID OXY OID OXY + NTX OID BID TOTAL (N = 50) (N = 102) (N = 102) (N = 102) (N = 356) BASELINE

N 50 102 1O2 101 355 MEAN 149.7 1418 149.3 141.4 145.O STANDARD DEVATION 41.75 37.28 33.50 39.35 37.56 MINIMUM 13.0 32.O 41.0 1O.O 1O.O MEDIAN 158.5 145.5 152.O 147.O 148.0 MAXIMUM 2OO.O 2OO.O 1970 2OO.O 2OO.O MODELP-VALUES

TREATMENT O.221 SEX O.O75 TREATMENT - SEX O688 PAIRWISE COMPARISON P-VALUES

PLACEBOOID O.266 O.993 O.149 OXY OID O.17O O686 OXY + NTX OID O.O75

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. 'P-VALUES FROM ANOVA MODEL WITH TREATMENT, SEX, AND TREATMENT + SEX INTERACTIONAS EFFECTS.

0372)

TABLE 15A

WOMAC OSTEOARTHRITIS PHYSICAL FUNCTION SUBSCALE - BY WEEK ANALYSIS POPULATION: INTENT TO TREAT POPULATION

PLACEBO OXY - NTX QID OXY OID OXY + NTX OID BID TOTAL (N = 50) (N = 102) (N = 102) (N = 102) (N = 356) ACTUAL VALUE AT WEEK 1

N 50 98 1OO 1OO 348 MEAN 1034.4 891.8 998.7 932.9 954.8 STANDARD DEVATION 431.11 423.35 378.56 413.37 410.74 MINIMUM 123.O 15.O 1490 52.0 15.O MEDIAN 1098.O 930.5 1098.5 955.5 1018.5 MAXIMUM 17OOO 1669.O 1658.0 1642.O 17OO.O MODELP-VALUES1 TREATMENT O.O85 SEX O622 TREATMENT - SEX O.771 PAIRWISE COMPARISON P-VALUES

PLACEBOOID O.O34 O640 O.136 OXY OID O.O40 O424 OXY + NTX OID O.204

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. 'P-VALUES FROM ANOVA MODEL WITH TREATMENT, SEX, AND TREATMENT + SEX INTERACTIONAS EFFECTS.

0373) US 2006/0009478 A1 Jan. 12, 2006 49

TABLE 15B

WOMAC OSTEOARTHRITIS PHYSICAL FUNCTION SUBSCALE - BY WEEK ANALYSIS POPULATION: INTENT TO TREAT POPULATION

PLACEBO OXY - NTX QID OXY OID OXY + NTX OID BID TOTAL (N = 50) (N = 102) (N = 102) (N = 102) (N = 356) ACTUAL VALUE AT WEEK 2

N 50 98 1OO 101 349 MEAN 985.O 847.6 910.6 834.4 881.5 STANDARD DEVATION 461.89 451.42 410.69 439.16 439.31 MINIMUM 57.4 16.O 54.O 17.0 16.0 MEDIAN 1038.O 88O.O 979.5 799.0 888.O MAXIMUM 17OOO 1669.O 1658.0 1646.0 17OO.O MODELP-VALUES

TREATMENT O.O99 SEX 0.457 TREATMENT - SEX O455 PAIRWISE COMPARISON P-VALUES

PLACEBOOID O.OFO O.471 O.036 OXY OID O.176 O.738 OXY + NTX OID O.088

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. 'P-VALUES FROM ANOVA MODEL WITH TREATMENT, SEX, AND TREATMENT + SEX INTERACTIONAS EFFECTS.

0374)

TABLE 1.5C

WOMAC OSTEOARTHRITIS PHYSICAL FUNCTION SUBSCALE - BY WEEK ANALYSIS POPULATION: INTENT TO TREAT POPULATION

PLACEBO OXY - NTX QID OXY OID OXY + NTX OID BID TOTAL (N = 50) (N = 102) (N = 102) (N = 102) (N = 356) ACTUAL VALUE AT WEEK 3

N 50 98 1OO 101 349 MEAN 939.9 82O.O 869.O 801.9 846.0 STANDARD DEVATION 534.35 468.67 452.25 458.64 471.41 MINIMUM 9.6 5.0 O.O 17.0 O.O MEDIAN 1004.O 867.O 969.5 776.O 89O.O MAXIMUM 17OOO 168O.O 1662.O 1671.O 17OO.O MODELP-VALUES

TREATMENT O.176 SEX O.238 TREATMENT - SEX O.38O PAIRWISE COMPARISON P-VALUES

PLACEBOOID O.131 O489 O.O52 OXY OID O.307 O604 OXY + NTX OID O.120

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. 'P-VALUES FROM ANOVA MODEL WITH TREATMENT, SEX, AND TREATMENT + SEX INTERACTIONAS EFFECTS.

0375) US 2006/0009478 A1 Jan. 12, 2006 50

TABLE 15D

WOMAC OSTEOARTHRITIS PHYSICAL FUNCTION SUBSCALE - BY WEEK ANALYSIS POPULATION: INTENT TO TREAT POPULATION

PLACEBO OXY - NTX QID OXY OID OXY + NTX OID BID TOTAL (N = 50) (N = 102) (N = 102) (N = 102) (N = 356) BASELINE

N 49 101 1O2 101 353 MEAN 1146.7 1101.7 1147.8 1142.9 1133.1 STANDARD DEVATION 34134 324.42 3O2.25 3O4.85 314.33 MINIMUM 208.O 208.O 1990 273.O 1990 MEDIAN 1180.0 1151.O 1187.5 1210.O 1187.O MAXIMUM 1688.O 17OOO 1659.O 165O.O 17OO.O MODELP-VALUES

TREATMENT O.837

TREATMENT - SEX O.936 PAIRWISE COMPARISON P-VALUES

PLACEBOOID O.474 O.929 O864 OXY OID O-435 O498 OXY + NTX OID O.918

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. 'P-VALUES FROM ANOVA MODEL WITH TREATMENT, SEX, AND TREATMENT + SEX INTERACTIONAS EFFECTS.

0376)

TABLE 1.6A

WOMAC OSTEOARTHRITIS TOTAL SCORE - BY WEEK ANALYSIS POPULATION: INTENT TO TREAT POPULATION

PLACEBO OXY - NTX QID OXY OID OXY + NTX OID BID TOTAL (N = 50) (N = 102) (N = 102) (N = 102) (N = 356) ACTUAL VALUE AT WEEK 1

N 49 98 1OO 99 346 MEAN 1468.6 1275.3 1418.5 1316.8 1355.9 STANDARD DEVATION 592.38 582.28 511.30 565.78 561.54 MINIMUM 214.O 2O.O 227.0 55.0 2O.O MEDIAN 1539.O 1312.5 1552.5 1323.O 1428.0 MAXIMUM 2398.O 23.47.O 234.O.O 2328.0 2398.O MODELP-VALUES

TREATMENT O.O85 SEX 0.576 TREATMENT - SEX O.782 PAIRWISE COMPARISON P-VALUES

PLACEBOOID O.O39 O664 O.119 OXY OID O.042 O.516 OXY + NTX OID O.162

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. 'P-VALUES FROM ANOVA MODEL WITH TREATMENT, SEX, AND TREATMENT + SEX INTERACTIONAS EFFECTS.

0377) US 2006/0009478 A1 Jan. 12, 2006 51

TABLE 1.6B

WOMAC OSTEOARTHRITIS TOTAL SCORE - BY WEEK ANALYSIS POPULATION: INTENT TO TREAT POPULATION

PLACEBO OXY - NTX QID OXY OID OXY + NTX OID BID TOTAL (N = 50) (N = 102) (N = 102) (N = 102) (N = 356) ACTUAL VALUE AT WEEK 2

N 50 98 1OO 1OO 348 MEAN 1399.O 1204.O 1283.O 1170.3 1245.O STANDARD DEVATION 649.08 626.06 557.71 611.83 608.7O MINIMUM 81.4 2O.O 99.O 55.0 2O.O MEDIAN 1483.O 1222.5 1309.O 1137.5 1257.0 MAXIMUM 24OOO 23.47.O 2346.0 2338.0 24OO.O MODELP-VALUES

TREATMENT O.O82 SEX O-463 TREATMENT - SEX OS46 PAIRWISE COMPARISON P-VALUES

PLACEBOOID O.O61 O.372 O.O23 OXY OID O.222 O.635 OXY + NTX OID O.O87

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. 'P-VALUES FROM ANOVA MODEL WITH TREATMENT, SEX, AND TREATMENT + SEX INTERACTIONAS EFFECTS.

0378)

TABLE 16C

WOMAC OSTEOARTHRITIS TOTAL SCORE - BY WEEK ANALYSIS POPULATION: INTENT TO TREAT POPULATION

PLACEBO OXY - NTX QID OXY OID OXY + NTX OID BID TOTAL (N = 50) (N = 102) (N = 102) (N = 102) (N = 356) ACTUAL VALUE AT WEEK 3

N 50 98 1OO 1OO 348 MEAN 1328.8 1164.9 1225.O 1121.0 1193.1 STANDARD DEVATION 750.67 651.16 624.27 638.73 656.O1 MINIMUM 17.6 6.O O.O 55.0 O.O MEDIAN 1468.O 1191.0 1312.O 1143.0 1231.5 MAXIMUM 24OOO 2368.O 2348.0 2364.O 24OO.O MODELP-VALUES

TREATMENT O.149 SEX O.2O1 TREATMENT - SEX O.410 PAIRWISE COMPARISON P-VALUES

PLACEBOOID O.129 O451 O.O39 OXY OID O341 O.S11 OXY + NTX OID O.204

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. 'P-VALUES FROM ANOVA MODEL WITH TREATMENT, SEX, AND TREATMENT + SEX INTERACTIONAS EFFECTS.

0379) US 2006/0009478 A1 Jan. 12, 2006 52

TABLE 16D

WOMAC OSTEOARTHRITIS TOTAL SCORE - BY WEEK ANALYSIS POPULATION: INTENT TO TREAT POPULATION

PLACEBO OXY - NTX QID OXY OID OXY + NTX OID BID TOTAL (N = 50) (N = 102) (N = 102) (N = 102) (N = 356) BASELINE

N 49 101 1O2 101 353 MEAN 1650.2 1569.6 1640.1 1627.O 1617.6 STANDARD DEVATION 445.37 432.36 382O2 397.20 409.67 MINIMUM 421.0 328.0 570-4 397.O 328.0 MEDIAN 1677.O 1640.O 1659.O 1703.O 1662.O MAXIMUM 2377.0 24OOO 233O.O 2273.O 24OO.O MODELP-VALUES

TREATMENT SEX TREATMENT - SEX PAIRWISE COMPARISON P-VALUES

PLACEBOOID O.330 O867 O.694 OXY OID O.315 O469 OXY + NTX OID 0.778

NOTE: DATA IMPUTED USING THE LASTOBSERVATION-CARRIED-FORWARD METHOD. 'P-VALUES FROM ANOVA MODEL WITH TREATMENT, SEX, AND TREATMENT + SEX INTERACTIONAS EFFECTS.

0380 The overall incidences of adverse events in all cations: dizziness, constipation, dry mouth, nausea, vomit three active treatment groups were generally comparable, ing, Somnolence, and pruritis. Table 17 ShowS adverse and the numerical differences observed are shown in the events experienced by >5% of the patients during Weeks 1, following tables. The most frequent adverse events (AES) 2, or 3 of treatment, based on the Intent To Treat Population. reported were those commonly associated with opioid medi

TABLE 1.7

Adverse Events Number (%) of Patients Oxycodone Plus Oxycodone Plus Adverse Event Placebo Oxycodone QID Naltrexone QID Naltrexone BID Days 1-3: 10 mg OXY/d Days 1-3: 10 mg OXY/d Days 1-3: 10 mg OXY/d Week 1, Placebo QID Days 4-8: 20 mg OXY/d Days 4-8: 20 mg OXY/d Days 4-8: 20 mg OXY/d Dose N 51 102 104 103 Constipation 2 (3.9) 13 (12.7) 5 (4.8) 11 (10.7) Dry Mouth 0 (0.0) 6 (5.9) 6 (5.8) 7 (6.8) Nausea 4 (7.8) 24 (23.5) 12 (11.5) 28 (27.2) Vomiting 2 (3.9) 4 (3.9) 2 (1.9) 8 (7.8) Fatigue 2 (3.9) 3 (2.9) 7 (6.7) 3 (2.9) Dizziness 0 (0.0) 17 (16.7) 16 (15.4) 31 (30.1) Headache 7 (13.7) 17 (16.7) 13 (12.5) 12 (11.7) Sommolence 2 (3.9) 16 (15.7) 12 (11.5) 12 (11.7) Pruritus 2 (3.9) 8 (7.8) 3 (2.9) 10 (9.7) Week 2, Placebo OID 30 mg OXY/d 30 mg OXY/d 30 mg OXY/d Dose N 45 85 84 74 Constipation 0 (0.0) 6 (7.1) 15 (17.9) 9 (12.2) Dry Mouth 0 (0.0) 4 (4.7) 2 (2.4) 5 (6.8) Nausea 1 (2.2) 12 (14.1) 3 (3.6) 10 (13.5) Vomiting 0 (0.0) 3 (3.5) 1 (1.2) 4 (5.4) Fatigue 3 (6.7) 0 (0.0) 1 (1.2) 1 (1.4) Dizziness 0 (0.0) 10 (11.8) 10 (11.9) 7 (9.5) Headache 3 (6.7) 3 (3.5) 5 (6.0) 3 (4.1) Sommolence 1 (2.2) 6 (7.1) 6 (7.1) 5 (6.8) Pruritus 0 (0.0) 5 (5.9) 3 (3.6) 5 (6.8) US 2006/0009478 A1 Jan. 12, 2006

TABLE 17-continued

Adverse Events Number (%) of Patients Oxycodone Plus Oxycodone Plus Adverse Event Placebo Oxycodone QID Naltrexone QID Naltrexone BID Week 3, Placebo OID 40 mg OXY/d 40 mg OXY/d 40 mg OXY/d Dose N 42 75 74 61 Constipation 1 (2.4) 2 (2.7) 9 (12.2) 3 (4.9) Dry Mouth 0 (0.0) 0 (0.0) 3 (4.1) 4 (6.6) Nausea 2 (4.8) 8 (10.7) 8 (10.8) 6 (9.8) Vomiting 1 (2.4) 9 (12.0) 2 (2.7) 2 (3.3) Dizziness 0 (0.0) 4 (5.3) 6 (8.1) 2 (3.3) Headache 3 (7.1) 6 (8.0) 1 (1.4) 3 (4.9) Sommolence 1 (2.4) 2 (2.7) 8 (10.8) 5 (8.2) Pruritus 0 (0.0) 3 (4.0) 1 (1.4) 7 (11.5)

0381. Seventy-nine of the 360 patients who received 0383. The study was also designed to investigate poten Study drug-discontinued treatment because of adverse tial opioid withdrawal effects when patients Stopped Study events (0 placebo; 29 oxycodone alone QID; 18 oxycodone drug without tapering at the end of treatment. The Short plus naltrexone QID and 32 oxycodone plus naltrexone Opioid Withdrawal Scale (SOWS) (see Table 6 above), BID). Oxycodone plus naltrexone QID had the lowest AE originally used for collecting withdrawal data from heroin discontinuation rate among the 3-active treatment group while oxycodone plus naltrexone BID and oxycodone alone addicts, was used to assess opioid withdrawal in this study. QID were comparable. Adverse events that resulted in the Although there were Statistically significant differences discontinuation of treatment in two patients or more in any between treatment groups, the differences were considered treatment group are shown in Table 18 below, based on the clinically insignificant because both the mean SOWS Intent to Treat Population. Most of the adverse events that changes and the differences of their changes were of small resulted in treatment discontinuation are commonly associ magnitude. The lack of clinically significant opioid with ated with the use of opioid , e.g., nausea, vomit drawal in this study is attributable to the relatively low ing, constipation, dizzineSS and Somnolence.

TABLE 1.8

Selected Adverse Events Number (%) of Patients Oxycodone Oxycodone Plus Oxycodone Plus System Organ Class Placebo QID Naltrexone OID Naltrexone BID Adverse Event N = 51 N = 102 N = 104 103 Any adverse event 0 (0.0) 29 (28.4) 18 (17.3) 32 (31.1) Eye disorders 0 (0.0) 0 (0.0) 2 (1.8) 0 (0.0) Gastrointestinal disorders 0 (0.0) 13 (12.7) 7 (6.7) 17 ( 6.5) Upper abdominal pain 0 (0.0) 0 (0.0) 0 (0.0) 2 ( .9) Constipation 0 (0.0) 1 (1.0) 0 (0.0) 2 ( .9) Diarrhea 0 (0.0) 0 (0.0) 2 (1.9) 0 (0.0) Nausea 0 (0.0) 7 (6.9) 4 (3.8) 12 ( 1.7) Vomiting 0 (0.0) 4 (3.9) 1 (1.0) 3 (2.9) General disorders and 0 (0.0) 2 (2.0) 0 (0.0) 2 ( administration site conditions Lethargy 0 (0.0) 0 (0.0) 0 (0.0) 2 ( .9) Nervous system disorders 0 (0.0) 8 (7.8) 11 (10.6) 14 ( 3.6) Dizziness 0 (0.0) 1 (1.0) 5 (4.8) 9 (8.7) Headache 0 (0.0) 2 (2.0) 2 (1.9) 0 (0.0) Sedation 0 (0.0) 2 (2.0) 0 (0.0) 0 (0.0) Sommolence 0 (0.0) 2 (2.0) 5 (4.8) 5 (4 Psychiatric disorders 0 (0.0) 1 (1.0) 3 (2.9) 0 (0.0) Euphoric mood 0 (0.0) 0 (0.0) 2 (1.9) 0 (0.0) Skin and subcutaneous 0 (0.0) 3 (2.9) 1 (1.0) 2 ( tissue disorders Pruritus 0 (0.0) 1 (1.0) 1 (1.0) 2 (

0382 Serious adverse events (SAEs) were reported for opioid doses and short treatment duration. Opioid with five patients. All of the Serious adverse events were unre drawal was not reported as an adverse event in any of the lated to treatment with Study medication. treatment groups. US 2006/0009478 A1 Jan. 12, 2006 54

0384. In summary, in this study oxycodone plus naltrex one BID was shown to be a safe and effective treatment for TABLE 2.0 patients with chronic pain and with Osteoarthritis of the hip or knee. Oxycodone plus naltrexone BID provided statisti Treatment QID Daily Dosing Scheme" cally and clinically significant reductions in pain intensity Group Upon Waking Noon Afternoon Bedtime compared to oxycodone alone QID when the same total daily dose of oxycodone was administered. The overall A. (OXY + NTX) Placebo (OXY + NTX) Placebo B (OXY + NTX) (OXY + (OXY + NTX) (OXY + NTX) incidence of opioid-related adverse events was comparable NTX) in the oxycodone plus naltrexone and oxycodone alone C (OXY + NTX) Placebo (OXY + NTX) Placebo treatment groups and no clinically meaningful effects on D OXY OXY OXY OXY Vital signs, laboratory Safety tests or QTc interval changes E NTX Placebo NTX Placebo were noted in the Oxycodone plus naltrexone or oxycodone F Placebo Placebo Placebo Placebo alone treatment groups. Oxycodone plus naltrexone BID Doses must be taken 30-60 minutes before meals and at least 4 hours provided better daily pain control to that of oxycodone alone apart. QID. Oxycodone plus naltrexone BID showed greater improvements in all categories of the WOMAC Osteoar 0390 Patients return to the clinic for weekly visits (tone thritis Index (pain, Stiffness and physical function) when day) for the first five weeks and then at 2-week (+two days) compared to the other active treatment groups. intervals for the remainder of the study (instead of the visit schedule described in Part A). At each clinic visit, quality of B. analgesia, pain control, and a global assessment of Study 0385 An additional clinical study was designed substan medication are collected as described above. The SF-12 tially the same as that described in Part A, with differences Health Survey and the WOMAC Osteoarthritis Index are indicated below. collected monthly (instead of at each clinic visit). 0386 The clinical study was designed as follows: (1) to 0391 Safety is evaluated as described in Part A. evaluate the efficacy and Safety of combinations of oxyc 0392 The Study Population is seven hundred fifty (750) odone (oxy) and naltrexone (ntX) when compared to oxyc patients with moderate to Severe chronic pain due to Osteoar odone, (2) to evaluate the efficacy and Safety of combina thritis of the hip or knee. According to the Study design tions of oxycodone (oxy) and naltrexone (ntx) administered described above, there are 150 patients each in the oxyc when compared to naltrexone, and (3) to compare the quality odone and naltrexone BID, oxycodone and naltrexone QID of life measures (WOMAC and SF-12) between treatment and oxycodone alone treatment groups, and 75 patients each groupS. in the naltrexone and placebo groups. 0387. A multicenter, randomized, double-blind, active 0393. The inclusion criteria are essentially the same as and placebo-controlled, clinical Study was designed and is described above in Part A, with the following exceptions: conducted. The Study evaluates the efficacy and Safety of an oral formulation of oxycodone and naltrexone relative to 0394 Patient agrees to refrain from taking any pain Oxycodone and to naltrexone over a 12-week fixed-dose medications other than Study drug during the 13-week period following one week of titration (instead of a three treatment period, rather than the shorter treatment week period). A total of 750 patients (instead of 360 patents) period of the clinical study of Part A. (Aspirin up to with chronic pain due to Osteoarthritis of the hip or knee are 325 mg/day is permitted for cardiovascular prophy enrolled into Six (instead of four) treatment groups: three laxis if at a stable dose one month prior to the Screening groups for combinations of oxycodone and naltrexone, a Visit.); and group for oxycodone alone, a group for naltrexone alone and 0395 Patient is able to ambulate for a specified dis a group for placebo. tance (at least 100 meters). 0388 Patients are randomly assigned to one of the six 0396 The exclusion criteria are essentially the same as treatment groups as shown in Table 19. described above in Part A, with the exceptions listed below. Additional eXclusion criteria are as follows: TABLE 1.9 0397) (a) Patient has a positive urine drug screen at the Treatment Weeks 1-12 Baseline/Titration Visit NOT caused by any therapeutic Group Titration (Fixed-Dose) medication permitted during the Study; A. (OXY 10 mg + NTX (OXY 20 mg + NTX 0.001 mg) BID 0.001 mg) BID 0398 (b) Patient has pain in the hip(s) or knee(s) B (OXY 5 mg + NTX (OXY 10 mg + NTX caused by conditions other than osteoarthritis, e.g., 0.001 mg) QID 0.001 mg) QID C (OXY 10 mg + NTX (OXY 10 mg + NTX malignancy, gout, inflammatory disease Such as rheu 0.001 mg) BID 0.001 mg) BID matoid arthritis, trauma, fibromyalgia, bony fracture, or D OXY 5 mg QID OXY 10 mg QID infection; E NTX 0.001 mg BID NTX 0.001 mg BID F Placebo OID Placebo OID 0399 (c) Patient has a history of cardiac disease (such as coronary artery disease, cardiomyopathy, congestive heart disease, valvular disease, arrythmia, etc.), angina, 0389 All treatment groups are scheduled for QID dosing myocardiac infarct (MI), cerebral aneurysm, cerebral to protect the double-blind study design as shown in Table vascular accident (CVA), transient ischemic event 2O. (TIA), inadequately controlled hypertension, or health US 2006/0009478 A1 Jan. 12, 2006 55

condition(s) which poses significant health risk in the respiratory rate (<8) or cyanosis, and (3) cardiac review by event of opioid withdrawal; assessing for heart rate <60, hypotension. If patients must be 04.00 (d) Patient has started or stopped physical terminated from the study, the Early Drug Termination therapy, transcutaneous electrical nerve Stimulation, assessments and opioid withdrawal monitoring (as needed) , osteopathic, acupuncture, or other are performed as discussed below. complementary treatment within the past four weeks or 0411. At the first visit, pre-enrollment screening is per is expected to undergo any changes in these therapies formed as described in Part A. in the duration of the study; 0412. The second visit is on the first day of the first 0401 (e) Patient has a psychiatric illness or medical titration period of the study. The patients returned to the illness/condition, and/or abnormal diagnostic finding, study center four to seven days after the Screening Visit for that, in the opinion of the investigator, would interfere completion of the pre-dose assessments. This visit included with the completion of the study, confound the results (1) obtaining a urine sample for drug screening using a rapid of the Study, or pose risk to the patient; drug screen kit (BioChek iCup TM Drug Screen). If positive for any drugs not caused by any therapeutic medication 0402 (f) Patient has a history of the following neo permitted during the Study, no further assessments are made. plastic disease: leukemia, lymphoma, or myeloprolif Patient cannot continue in the study; (2) reviewing the erative disease, metastatic cancer. In patients with take-home diary from the past four to Seven days; (3) collect treated localized malignancies, the decision to exclude bottle of acetaminophen and perform accountability, (4) is made by the Sponsor on individual cases, and baseline clinic PI rating, and (5) reviewing inclusion and 0403) (g) Patient has AST, ALT, GGT, or alkaline exclusion criteria. This assessment also includes verifying phosphatase >2 times the upper limit of normal; hema that (a) the mean daily overall pain intensity Score collected tocrit <30%; or creatinine >1.8 at the Screening Visit. in the diary over the last two days of the 4- to 7-day washout The following exclusion criteria in the clinical Study period is 25 (on a scale of 0 to 10) while off all analgesic describe of Part A were modified or omitted for the medications (except acetaminophen as directed); (b) the present clinical Study: clinic PI at this visit measures 25 (on a scale of 0 to 10); and (c) checking that the clinical laboratory tests results from the 0404 (a) Acute hepatitis is not included in the exclu Screening Visit are without significant clinical abnormalities, Sion factors, and that the urine pregnancy test is negative (if required). 0405 (b) History of severe hepatic or renal impairment 0413 Patients meeting the study entry criteria are ran is not included in the exclusion factors, domly assigned to one of the Six treatment groups, and are 0406 (c) “Patient had other diseases significant assigned a randomization number and Study medication kit enough, in the opinion of the Investigator, to pose a risk number. The following assessments are then conducted: (1) for the administration of study drug or that will inter a brief (interim) medical history; (2) vital signs; (3) review fere with pain assessments, is not included in the and record concomitant medications; (4) SF-12 Health Sur exclusion factors, vey; and (5) WOMAC Osteoarthritis Index. 0407 (d) Patient has a history of gastric, biliary, or 0414. Once these assessments and procedures are com Small intestine Surgery, or any other diseases that cause pleted, the Study medication kit is dispensed for the titration clinical malabsorption is an exclusion factor (rather period. The patients received their take-home daily diaries than “Patient had chronic biliary tract disease, chronic and are provided with an appointment card for the next visit. pancreatitis, or inflammatory bowel disorders”); and The study nurse thoroughly reviewed each section of the diary with the patient. The daily diary issued at Visit 2 is 0408 (e) Patient's history of alcohol or drug abuse is used to record the following information at bedtime imme within the past 5 years, diately prior to dosing: (1) overall PI in the past 24 hours; 04.09 The physical descriptions of the drugs used for the and (2) adverse events. Study are as follows. For the washout period, acetaminophen is dispensed as described in Part A. The investigational drug 0415 Patients return to the study center at the end of Supplies are in tablet dosage forms containing oxycodone titration (tone day) for the following: HCl and naltrexone HCl, oxycodone HCl, naltrexone or 0416 (1) opioid toxicity assessment; placebo. All of the tablet dosage forms are indistinguishable from one another to facilitate blinding. Tablets are arranged 0417 (2) review take-home diary (including overall on each blister card by Study Day and contain four doses per daily bedtime PI and opioid-related adverse events); day. Each blister card also contains three days of extra Study 0418 (3) record new/changed adverse events and con drug to allow for flexibility in planning return clinic visits. comitant medications, The extra Study drug must remain intact within its original packaging So that it may be returned during each clinic visit. 0419 (4) collect study medication from previous week The investigational drug Supplies are dispensed in these kits. and account for used/unused Supplies, 0410 Safety procedures include those described in Part 0420 (5) vital signs; A. The opioid toxicity assessment includes: (A) CNS review by assessing for (1) confusion, altered mental State, (2) 0421 (6) quality of analgesia; excessive drowsiness, lethargy, stupor, (3) Slurred speech (new onset), (B) respiratory review by assessing for (1) 0422 (7) pain control; hypoVentilation, shortness of breath, apnea, (2) decreased 0423 (8) global assessment of study medication; US 2006/0009478 A1 Jan. 12, 2006 56

0424 (9) dispense take-home daily diary; and that the patient return to the clinic within 24 hours of Stopping the Study medication and complete the end of Study 0425 (10) dispense one blister card of study medica assessments described above. For patients who have been on tion (by telephoning IVRS). study medication for >4 weeks, Day 1 of the opioid with 0426. At the conclusion of this visit, the patient is given drawal monitoring period begins 24 hours after the last dose an appointment card for the next study Visit. of Study medication. The investigator can request that the 0427 Patients return to the study center at weekly inter patient remain in the Study for the post-treatment follow-up vals (tone day) for 4 weeks (Visits 4-7) and at the end of Visit. Study drug assigned to patients who discontinue early Weeks 6, 8, and 10 (two days) (Visits 8-10) for the may not be reassigned. aSSeSSments: 0448. The primary analysis population is the intent-to treat (ITT) population. The ITT population will consist of all 0428 (1) opioid toxicity assessment; patients who take Study medication and are used for both 0429 (2) review take-home diary (including overall efficacy and Safety analyses. In the event that a patient is daily bedtime PI and opioid-related adverse events); randomized incorrectly or is administered the incorrect Study medication, the patient is analyzed according to the 0430 (3) record new/changed adverse events and con Study drug actually received. Additional analysis popula comitant medications, tions may be defined as appropriate based on the actual Study 0431 (4) collect study medication from previous week experience. and account for used/unused Supplies, 0449 Demographic variables and patient characteristics 0432 (5) vital signs; are Summarized descriptively by treatment group and over all. Demographic variables will include age, weight, height, 0433 (6) quality of analgesia; gender, and race/ethnicity. Baseline characteristics includes 0434 (7) pain control; the PI score recorded in the clinic and baseline values of efficacy variables. Baseline and post-baseline patient char 0435 (8) global assessment of study medication; acteristics includes Study drug administration and prior and 0436 (9) SF-12 Health Survey; concomitant medications. 0437 (10) WOMAC Osteoarthritis Index; 0450. The following endpoints are summarized and ana 0438 (11) dispense take-home daily diary; lyzed: 0439 (12) dispense one blister card of study medica 0451 (1) Daily diary PI score- The daily PI assess tion (by telephoning IVRS). Two blister cards are ments are analyzed as weekly values as follows. For dispensed at the End of Week 4 Visit. each post-baseline week, the PI recorded during the last two days of dosing within the week are averaged. 0440 At the conclusion of each visit, the patient is given Baseline PI is defined as the average PI recorded during an appointment card for the next study Visit. the two days immediately prior to the Baseline/Titra 0441 Patients return to the study center at either the end tion visit; of Week 12 (+two days) or after early drug termination for the Same End of Treatment assessments described above 0452 (2) Quality of analgesia-assessed and analyzed except that a blood Sample for PKanalysis is not taken, and by clinic visit (weekly for the first five weeks and SOWS is only performed if the subject is on the study drug biweekly thereafter); 24 weeks. 0453 (3) Pain control-assessed and analyzed by 0442. At the conclusion of this visit, prior to departing the clinic visit (weekly for the first five weeks and center, the patient is given an appointment card for the next biweekly thereafter); Study visit. Patients are instructed to contact the Study center 0454 (4) Global assessment of study medication immediately if they experience Severe signs and Symptoms assessed and analyzed by clinic visit (weekly for the of opioid withdrawal. first five weeks and biweekly thereafter); 0443) For four days after the last dose of study medica tion, the Study center contacts patients as described in Part 0455 (5) SF-12 Health Survey-assessed and ana A to monitor for Symptoms of opioid withdrawal. lyzed monthly; Scored as described in the documenta tion (e.g., Ware et al., 1998); and 0444 Patients return to the study center approximately one week (ttwo days) after the last dose of Study medication 0456 (6) WOMAC Osteoarthritis Index-assessed and for a post-treatment follow-up visit (Visit 12). At this visit, analyzed monthly; calculated per the WOMAC User the following assessments are completed: Guide. 0445 (1) review take-home diary; and Missing efficacy data is imputed using the last-observa tion-carried-forward (LOCF) approach. If the number 0446 (2) record new/changed adverse events and con of patients per center is Small, centerS may be pooled comitant medications. for analysis, or omitted from Statistical models. Unless 0447 Patients may choose to discontinue study drug or otherwise indicated, all testing of Statistical hypotheses Study participation at any time, for any reason, Specified or is two-sided, and a difference resulting in a p-value of unspecified, and without prejudice. If a patient chooses to less than or equal to 0.05 is considered Statistically discontinue Study drug early, the investigator must request Significant. US 2006/0009478 A1 Jan. 12, 2006 57

0457 For primary analysis of data, the primary efficacy of oxycodone and naltrexone; and (4) consistency of the endpoint is the percent change from baseline to Visit 11 half-life and clearance of oxycodone over the course of the (Week 12 or early drug termination) in average daily PI. An Study. The relationships between clinical outcomes and the analysis of covariance (ANCOVA) model is employed, as plasma concentrations of oxycodone, oxymorphone, and described below. The pairwise treatment comparison that is 6f-naltrexol were plotted for each treatment as shown in of primary interest is treatment group A(OXY20 mg+NTX FIGS. 8 to 10. 0.001 mg during the fixed-dose period) vs. treatment group 0463 Patients with moderate-to-Severe pain due to D (OXY 10 mg QID during the fixed-dose period). Osteoarthritis of the hip or knee were randomly assigned to 0458 For secondary analysis of data, the average daily one of four treatment groups as shown in Table 3 of Example PI, SF-12 Health Survey, and WOMAC Osteoarthritis Index 1. Plasma Samples were obtained for each patient at the is analyzed in terms of the values themselves as well as in beginning of WeekS 1, 2, 3 and at the end of dosing during terms of change and percent change from baseline. These Week 3. variables are Summarized descriptively by treatment group and by SeX. Treatments are compared globally and in pair 0464) Patients for inclusion in the bioanalytical analyses wise fashion at each time point using an analysis of cova (24/sex/treatment arm) were randomly selected from those riance (ANCOVA) model that includes treatment, center, who completed all three weeks of treatment in each of the and SeX as factors and baseline value as a covariate. Potential three active treatment arms. Plasma Samples randomly interactions are assessed by also fitting a model with the Selected from each of those treatment arms were analyzed Same main effects and with the treatment by center, treat for oxycodone, oxymorphone, norOxycodone, naltrexone ment by Sex, and treatment by baseline interaction terms. In and 6.3-maltrexolby validated coupled Solid phase extraction addition, pairwise t-tests are used to compare each post LC-MS/MS methods. baseline time point to each prior time point, within treatment 0465 For the analysis of linearity and dose proportion group, overall and by SeX. ality, linear equation coefficients were obtained by averaging 0459. The quality of analgesia, pain control, and global patient-specific slopes and intercepts obtained by within assessment of Study medication are Summarized descrip patient least Squares regression. This was done to account tively by treatment group, overall and by Sex. Treatments are for the correlation among the repeated measurements due to compared at each time point using the Cochran-Mantel the patient's contributing data at each dose level. The Haenszel row mean Scores test, using equally Spaced Scores, resulting Slopes among treatment groups were compared by stratified by sex. Cochran-Mantel-Haenszel row mean one-way analysis of variance (ANOVA), and a one-sample Scores tests will also be used to compare each post-baseline t-test assessed the common Slope's difference from Zero. A time point to each prior time point, within treatment group, measure of deviation from linearity was constructed as the overall and by sex. difference between the concentration at the middle dose Versus the average of the concentrations at the lower and 0460 Sensitivity analyses are carried out to determine the higher doses. Due to equal spacing of doses, this measure extent to which the Statistical analysis results are influenced by the choice to impute missing observations using LOCF. has expectation Zero under the hypothesis of linearity. AS The primary analysis is repeated using one or more alter above, ANOVA and t-tests were used to assess linearity. native imputation methods (e.g., imputing data following 0466. The relationship between oxycodone plasma con withdrawal depending on the reason for withdrawal) and centration and various outcome measures were assessed by using an appropriate longitudinal analysis technique Such as Pearson correlation coefficients and associated p-values. For repeated measures mixed-effects analysis of variance. In these analyses, the plasma concentration data were log addition, an “observed data' analysis, without any data transformed in order to achieve approximately Gaussian imputation, is conducted on Selected endpoints using the distributions. Oxycodone plasma concentrations (ignoring Same analysis methods described previously. time of blood draw) in active treatment arms were compared by one-way ANOVA. Regression analyses combined with 0461 Adverse events are reported and examined as F-tests on the extra Sums of Squares assessed whether described in Part A. Change from baseline is summarized profiles and correlations differed among active treatment descriptively for vital signs and QTc interval. Laboratory arms. P-values were computed without adjustment for mul data is Summarized descriptively on the original Scale, tiple testing. Similar analyses were conducted on the oxy change from baseline, and in terms of the normal range. morphone and 6B-naltrexol plasma concentrations. EXAMPLE 2 0467. The oxycodone and oxymorphone plasma concen 0462. A clinical study was conducted as described in tration data showed a skewed distribution commonly Seen in Example 1 wherein Safety and analgesic effects of oxyc pharmacokinetic data. The base-10 log transformation odone or a combination of oxycodone and naltrexone were reduced the skewness on the right tail (larger concentrations) measured in patients with chronic pain as described in but introduced skewness on the lower tail. To achieve Example 1. Plasma concentrations of the administered drugs Symmetry, modified log transformations were used. Sym and their major metabolites were measured to determine: (1) metry was achieved using the following modified log trans Oxycodone absorption from the combination drug of oxyc formations: odone and naltrexone; (2) dose proportionality of plasma 0468 Transformed oxycodone value=log(original concentrations of oxycodone and oxymorphone from the value--10)-log(10) combination drug of oxycodone and naltrexone; (3) achieve ment of Steady State of plasma concentrations of Oxycodone, 0469 Transformed oxymorphone value=log(original Oxymorphone and 6(3-maltrexol from the combination drug value--0.1)-log(0.1) US 2006/0009478 A1 Jan. 12, 2006 58

0470 Transformed 6B-naltrexol value=log(original value). FIG. 5 shows the box-and-whisker plots of the value). transformed plasma concentrations of oxymorphone for each treatment group. The median log-transformed plasma 0471) The translations by -log(10) and -log(0.1) were concentrations of oxymorphone are not different following used So that concentrations of Zero on the original Scale the final dose for each treatment arm (* indicates outlying would be transformed to zero. The transformation for value). As shown in FIG. 6, the plasma concentrations of 6f-naltrexol did not require a translation to achieve an Oxycodone and oxymorphone normalized by dose remained approximately Gaussian distribution. constant throughout the Study, irrespective of treatment 0472. In addition to Summary statistics and graphs, box group, Suggesting that Steady State is achieved and main and-whisker plots were used to Summarize the distribution tained. As shown in FIG. 7, the plasma concentrations of of variables. Those figures depict either the minimum value 6f-naltrexol, the major metabolite of naltrexone and a in the data or Selected outliers at the lower end, the quartile marker for its concentration, remained constant throughout (25th percentile), the median, the upper quartile (75th per the Study (sampled at the end of each treatment week). centile) and the maximum or selected outliers at the upper Maintenance of constant concentrations of 6f-naltrexol, the end. major metabolite of naltrexone, Suggests that naltrexone 0473 Statistical analyses except extra sum of squares reached steady state by the end of Week 1 regardless of a analyses were performed using MINTAB(R), release 14.1 2-fold difference in dose and dosing frequency between (Minitab Inc., 2003). The extra sum of squares analyses treatmentS. were calculated using Microsoft Excel, with MINTAB(R) 0476. There was no statistically significant difference Sum of Squares input. among treatment groups for any of the correlations between 0474 As shown in FIGS. 1 and 2, the mean plasma measures of clinical efficacy verSuS plasma concentrations concentrations of oxycodone and oxymorphone from each of oxycodone or oxymorphone (p20.193). For the efficacy drug increased linearly with increasing dose levels over the measurements shown in FIG. 8, the plasma concentrations course of the Study. Oxycodone dose levels increase during of oxycodone correlated only with global assessment and the course of the Study; the oxycodone dose per dose of the quality of analgesia. The lines in each plot panel of FIG. 8 combination drug of oxycodone and naltrexone BID was 5 are least Square fits. For the efficacy measurements shown in mg (days 1-3), 10 mg (days 4-8), 15 mg (week 2) and 20 mg FIG. 9, there was no correlation between the plasma con (week 3). The total daily dose of oxycodone was equal in centrations of oxymorphone and those efficacy measure active treatment arms, i.e., the oxycodone dose in individual ments. The lines in each plot panel of FIG. 9 are least square doses of the combination drug of oxycodone and naltrexone fits. QID or oxycodone QID was half that of the combination 0477 The mean 6B-naltrexol plasma concentration in the drug of oxycodone and naltrexone BID. The relationship BID group is statistically different from that in the QID between the oxycodone plasma concentrations and the group (p<0.001, t-test of log-transformed plasma concen amount of oxycodone in the dosage form was estimated as: trations). There was also a significant difference between the plasma concentration of oxycodone (ng/mL)=2.28+ two groups in pain intensity reduction. In addition to these 0.4223(dose of oxycodone, mg/day). The slope was statis group differences, the relationship between 6B-maltrexol tically significant (p<0.001, t-test) and slopes did not differ concentrations and clinical outcomes can be observed in the significantly among treatments (p=0.258, ANOVA). The test individual patients, with lower plasma concentrations of for deviation from linearity was not Statistically significant 6?-naltrexol corresponding to greater clinical efficacy (e.g., (p=0.787, t-test). The relationship between the oxymor pain relief) as shown in FIG. 10. The lines in each plot panel phone plasma concentrations and the amount of oxycodone of FIG. 10 are least square fits. in the dosage form was estimated to be: plasma concentra tion of oxymorphone (ng/mL)=0.0607+0.007153(dose of 0478 As shown in the above-described figures, the simi oxycodone, mg/day). The slope was statistically significant larity of oxycodone and oxymorphone plasma concentra (p<0.001, t-test) and the slopes did not differ significantly tions after administration of the combination drug of oxy among treatments (p=0.163, ANOVA). The outcome for the codone and naltrexone BID versus oxycodone QID indicates test for deviation from linearity was (p=0.056, t-test). The that the absorption of oxycodone from the combination drug linear equation coefficients were obtained by averaging of oxycodone and naltrexone was Similar to absorption from patient-specific slopes and intercepts obtained by within Oxycodone alone. The plasma concentrations of oxycodone patient least Squares regression. and Oxymorphone increased linearly with dose, demonstrat ing that the exposure to oxycodone from the combination 0475 FIG. 3 shows the box-and-whisker plots of the drug of oxycodone and naltrexone is proportional to dose. plasma concentrations for oxycodone for each treatment Maintenance of dose proportionality of oxycodone and group. FIG. 4 shows the box-and-whisker plots of the Oxymorphone throughout the Study Suggests that Steady transformed plasma concentrations for Oxycodone for each State was achieved during each dose interval. The consis treatment group. The results in FIGS. 3 and 4 show that tency of dose proportionality also indicates that the oxyc there was no statistical difference (ANOVA, p=0.492) odone elimination half-life did not change during the course among active treatment groups for Oxycodone plasma con of the Study. Likewise, the uniform concentrations of 6f-nal centrations. AS shown in FIG. 3, the median plasma con trexol, the major metabolite of naltrexone, Suggest that centrations of oxycodone are not different following the final maltrexone had attained steady state by the end of Week 1 for dose for each treatment group (* indicates outlying value). both doses and dosing frequencies. As shown in FIG. 4, the median log-transformed plasma concentrations of oxycodone are not different following the 0479 Plasma concentrations of oxycodone and its final dose for each treatment group (* indicates outlying metabolites, as well as the major metabolite of naltrexone US 2006/0009478 A1 Jan. 12, 2006 59

(6f-naltrexol) showed stable pharmacokinetic parameters Concentration Concentration indicating that the dosage regimens for the combination drug Transformed Value (ng/ml) (ng/ml) of oxycodone and naltrexone are predictable and easy to O.O O.O O.OO manage. Comparisons of the BID and QID dosing regimens O.1 2.6 O.O3 for the combination drug of oxycodone and naltrexone O.2 5.8 O.O6 showed good correlation between 6B-maltrexol concentra O.3 1O.O O.10 0.4 15.1 O.15 tion and Statistically significant reduction in pain intensity 0.5 21.6 O.22 and the percentage change in pain intensity. O.6 29.8 O.30 O.7 40.1 O.40 0480. The dissimilar clinical response in the presence of O.8 53.1 O.53 Similar oxycodone exposures Suggests that the naltrexone/ O.9 694 O.69 6f-naltrexol concentrations are important in determining the 1.O A. O.90 1.1 A. 1.16 threshold for clinical efficacy. 1.2 A. 1.48 0481. The studies described in this Example show that 1.3 A. 1.90 oxycodone and naltrexone were well-absorbed from the combination drug of oxycodone and naltrexone and that plasma concentrations of oxycodone, oxymorphone and 0484 Pharmacodynamic outcome measures as described 6f-naltrexol from the combination drug of oxycodone and in Example 2 and FIGS. 8-10 were paired with the appro naltrexone increased directly proportional to the dose and priate analyte plasma concentrations for PK/PD analyses. reached Steady State over each dosing interval. Clearances The plasma concentrations of oxycodone, oxymorphone, and apparent half-lives of oxycodone, Oxymorphone and naltrexone and 6(3 maltrexol were measured. It has been 6f-naltrexol from the combination drug of oxycodone and observed that plasma concentrations of naltrexone are about naltrexone did not change over the course of the Study and one-tenth the plasma concentrations of 6f-naltrexol in the dose and dosage regimen for the combination drug of Same plasma Samples. Accordingly, 6(3-maltrexol plasma Oxycodone and naltrexone BID resulted in Significantly concentrations are useful as indicators of naltrexone plasma greater clinical efficacy compared to the QID regimen in concentrations and to identify preferred plasma concentra reduction in pain intensity or percentage change in pain tions of naltrexone. intensity. Plasma concentrations of oxycodone and oxymor phone did not correlate with greater pain relief and the 0485 Included in the PK/PD analytes were oxycodone lowest dose of naltrexone (from the administration of the and oxymorphone plasma concentrations individually paired combination drug of oxycodone and naltrexone BID) uti with: pain intensity at final Visit, pain intensity percent lized in this study resulting in the lowest plasma concentra change from baseline at final visit, patient's global assess tions of 6f-naltrexol, as a measure of naltrexone plasma ment at final visit; quality of analgesia at final visit; concentrations, corresponded to greater pain relief. WOMAC-pain at final visit; WOMAC-pain percent change from baseline at final visit, WOMAC-stiffness at final visit; EXAMPLE 3 WOMAC-stiffness percent change from baseline at final 0482 Data were obtained from a clinical study conducted visit; WOMAC-physical function at final visit; WOMAC as described in Examples 1 and 2. Plasma concentrations of physical function percent change from baseline at final visit; the administered drugs and their major metabolites were WOMAC-total score at final visit; and WOMAC-total score measured by validated Solid phase extraction coupled percent change from baseline at final visit. Among the HPLC-MS/MS. As described in this Example, pharmacoki subjects from whom blood was drawn for determination of netic/pharmacodynamic (PK/PD) analyses, including novel plasma concentrations, the times from the last dose of the applications of modeling analysis, provide novel methods Study drug administered to the blood draw were recorded. and materials for treating chronic pain, including but not Times are centered on the hour (e.g., hour 4 covers times limited to novel dosage forms and methods of administra from 3.5 up to but excluding 4.5 hours). Table 22 Summa tion. rizes the times from last dose to blood draw by treatment group for those Subjects with plasma concentration data. 0483 AS described in Example 2, the oxycodone and There was no significant difference among the three treat Oxymorphone plasma concentration data showed a skewed ment groups in time from last dose to blood draw. distribution commonly seen in pharmacokinetic (PK) data. To achieve Symmetry, modified log transformations were TABLE 22 used as described in Example 2. AS noted in Example 2, 6f-naltrexol plasma concentrations did not require transfor Number of Patients with Plasma Concentration Data by Hour and mation to achieve an approximately Gaussian distribution. Treatment Table 21 shows the correspondence between the transformed Oxycodone + Oxycodone + and original Scales (where “a” indicates beyond range of Oxycodone Naltrexone Naltrexone observed data). Hour Total QID BID QID 1. 19 7 5 7 TABLE 21 2 31 7 8 16 3 29 7 13 9 Data Transformations of Oxycodone and Oxymorphone Concentrations 4 24 11 6 7 5 15 6 5 4 Original Original 6 8 4 2 2 Oxycodone Oxymorphone >=6.5 1O 3 5 2 US 2006/0009478 A1 Jan. 12, 2006 60

puted without adjustment for multiple testing. Similar analy TABLE 22-continued SeS were conducted on the oxymorphone plasma concentra tions. Number of Patients with Plasma Concentration Data by Hour and Treatment 0488 A Kruskal-Wallis test was used to compare active Oxycodone + Oxycodone + treatment arms with respect to time from last dose to blood Oxycodone Naltrexone Naltrexone draw. The main PKassessment used linear regression analy Hour Total QID BID QID sis to fit the time-concentration profiles. One-way analysis All 136 45 44 47 of variance (ANOVA) was used to compare active treatment arms with respect to average oxycodone and oxymorphone plasma concentration (ignoring time of blood draw). Pear 0486 As described in Example 2, for the analysis of Son correlation coefficients and associated p-values were linearity and dose proportionality, linear equation coeffi used to describe the relationship between plasma concen cients were obtained by averaging patient-specific slopes and intercepts obtained by within-patient least Squares tration versus the outcome measures. Regression analyses regression. This was done to account for the correlation combined with F-tests on the extra Sums of Squares were among the repeated measurements due to the patient's used to assess whether the time-concentration profiles and contributing data at each dose level. The resulting slopes correlations differed among the three active treatment arms. among treatment groups were compared by one-way analy P-values were computed and reported without adjustment sis of variance ANOVA), and a one-sample t-test assessed for multiple testing. AS described in Example 2, Statistical the common Slope's difference from Zero. A measure of analyses except extra Sum of Squares analyses were per deviation from linearity was constructed as the difference formed using MINITABOR, release 14.1. The extra sum of between the concentration at the middle dose versus the Squares analyses were calculated using MicroSoft Excel, average of the concentrations at the lower and higher doses. with Minitab Sums of Squares as input. Due to equal spacing of doses, this measure has expectation 0489 Statistically significant correlations (r=0.21, Zero under the hypothesis of linearity. As above, ANOVA p=0.005) were observed between transformed oxycodone and t-tests were used to assess linearity. concentration and each of the measures Patient's Global 0487. As also described in Example 2, the relationship ASSessment and Quality of Analgesia (which are pharma between oxycodone plasma concentration and various out codynamic data), at the final visit. Correlations for the other come measures were assessed by Pearson correlation coef outcome measures were close to Zero and not statistically ficients and associated p-values. For these analyses, the Significant. The calculation of these correlation coefficients plasma concentration data were log-transformed in order to included placebo data with imputed oxycodone concentra achieve approximately Gaussian distributions. Oxycodone tions of 0.0. In an analysis that excluded the placebo plasma concentrations (ignoring time of blood draw) in patients, the correlations were Smaller and leSS Significant. active treatment arms were compared by one-way ANOVA. Table 23 lists the correlation coefficients. There was no Regression analyses combined with F-tests on the extra Statistically Significant difference among treatment arms in Sums of Squares assessed whether profiles and correlations these plasma concentration and measures of efficacy rela differed among active treatment arms. P-values were com tionships.

TABLE 23 Correlation Coefficients vs Transformed Oxycodone Concentration Pharmacodynamic outcome All Oxycodone All except measure' Patients QID Oxycodone + Naltrexone BID Oxycodone + Naltrexone QID placebo Pain Intensity at final visit -0.084 -0.014 O.143 -O.057 O.O1O O.263 0.927 O.353 O.703 O.912 Paint intensity percent -0.102 -0.085 O.O8O -0.084 -0.044 change O.176 0.579 O605 0.575 O612 Global assessment at final O.209 O.174 0.055 O.147 O.124 visit O.OOS O.254 0.722 O.323 O.150 Quality of analgesia at final 0.211 0.2O7 -OOO9 O.145 O.114 visit O.OOS 0.172 O.954 O.332 O.185 WOMAC-Pain at final visit -0.070 -0.049 O.192 -O.230 -0.044 O.356 O.748 O.213 O.12O O611 WOMAC-Pain percent -O.O57 -0.040 O.196 -O.237 -0.044 change O451 0.793 O.2O3 O.109 O612 WOMAC-Stiffness at final -0.070 -O.O3O O.088 -0.151 -O.O38 visit O352 O.844 0.573 O.312 O.665 WOMAC-Stiffness percent -0.042 O.102 O.O78 -0.208 -0.015 change 0.576 O.SO6 O618 O.162 O865 WOMAC-Physical -O.O71 -0.036 O.123 -0.216 -O.OSS functioning at final visit O.345 O.815 O433 O.145 0.529 WOMAC-Physical -O.O60 O.O15 O.O89 -0.211 -0.044 functioning percent change O.426 O.924 0.570 0.155 O.615 WOMAC-Total score at -O.O72 -0.038 O.137 -0.215 -0.052 final visit O343 O.8O2 O.381 O.147 0.551 US 2006/0009478 A1 Jan. 12, 2006 61

TABLE 23-continued Correlation Coefficients vs Transformed Oxycodone Concentration Pharmacodynamic outcome All Oxycodone All except measure' Patients QID Oxycodone + Naltrexone BID Oxycodone + Naltrexone QID placebo WOMAC-Total score -0.062 O.O1O O.125 -0.249 -0.044 percent change O.417 O948 O.425 O.O91 O.614 "For each pharmacodynamic outcome measure, the first row of data displays correlation coefficients, and the second row dis plays corresponding p-values.

0490 The concentration time course of oxymorphone change in pain intensity was the drug effect used in a was well modeled by a Straight line. Separate regression modeling analysis of plasma concentration VS. drug effect. lines were also fit for each treatment group. Observed differences in Slope are not statistically Significant. Overall, ignoring time of blood draw, there was no Statistically Significant difference among active treatment arms in trans formed Oxymorphone plasma concentration. None of the correlations between oxymorphone and outcome measures was Statistically significant, as shown in Table 24. There was no Statistically significant difference among treatment arms in these PK/PD relationships.

TABLE 24 Correlation Coefficients vs Transformed Oxymorphone Concentration Pharmacodynamic outcome All Oxycodone Oxycodone + Naltrexone Oxycodone + Naltrexone All except measure' Patients QID BID QID placebo Pain Intensity at final visit -0.044 O.293 -O.095 O.O2 0.079 O.S60 O.O51 O.540 O.889 O.359 Paint intensity percent change -O.O28 O.228 -O.O99 O.O6 O.O76 O.709 O.131 OS21 O.685 0.379 Global assessment at final visit O140 -0.126 0.297 -0.17 O.O11 O.O63 O.410 O.O51 O.25 O.898 Quality of analgesia at final visit O.130 -0.126 O.23O -0.144 -0.015 O.O85 O.409 O.134 O.333 O.863 WOMAC-Pain at final visit -O.O28 O.148 -0.041 -O.O74 O.O26 O.711 O.332 O.789 O.623 O.766 WOMAC-Pain percent change O.OO7 O.153 -0.036 -OOO2 O.O60 O.93O O.317 O.817 O.99 O.491 WOMAC-Stiffness at final visit -0.045 0.155 -0.141 -O.O18 O.OOS 0.553 O.308 O.366 O.905 O.953 WOMAC-Stiffness percent -O.O26 O.215 -O-170 O.OO2 O.O12 change O.73O 0.157 0.275 O.989 O.891 WOMAC-Physical functioning at -0.045 O.139 -0.146 -0.05 -0.011 final visit O.548 O.364 O.349 O.734 O.896 WOMAC-Physical functioning -O.O17 O.184 -0.221 O.139 O.O26 percent change O818 0.227 O.154 O.350 0.765 WOMAC-Total score at final visit -0.043 O.143 -0.129 -0.053 -OOO3 0.574 O.347 O411 O.723 0.973 WOMAC-Total score percent -0.021 O.184 -0.174 O.O59 O.O23 change O.782 0.227 O.264 O.692 O.794 "For each pharmacodynamic outcome measure, the first row of data displays correlation coefficients and the second row dis plays corresponding p-values. 0491 Pharmacokinetic and pharmacodynamic data (e.g., percentage change in pain intensity) associated with the administration of oxycodone and naltrexone in clinical Stud ies as described above were evaluated to identify desirable parameters involving dosage forms comprising naltrexone. Table 25 shows 6B-naltrexol plasma concentrations from the randomly Selected Samples for the Subjects receiving oxy codone and naltrexone. Table 25 also shows pain intensity measurements for those Subjects, including pain intensity baseline, final pain intensity, and the percent change in pain intensity. AS discussed in more detail below, the percent

US 2006/0009478 A1 Jan. 12, 2006 63

TABLE 25-continued PK/PD Data For Combination Drug of Oxycodone and Naltrexone In QID and BID Dosing Regimens Time from Pain Int Pain Int Subject Treatment Sex Last Dose Base Final Pain Int Percent 6BNaltrexol O32-0543 OID F 3.42 8 9 2.5 3.35 O32-0709 OID F 2.25 9 5 -44.444 3.38 O33-OO12 OID M 6.92 7 4 -42.857 181 O33-0546 OID F 2.42 8 5 -37.5 3.23 O35-OO63 BID M 8 7 2 -71.429 O.63 O35-OO72 BID M O.92 7 4 -42.857 O35-0594 BID F 2.13 9 3 -66.667 2.33 O37-OO52 OID M 1.17 8 4 -50 2.5 O37-OO74 OID M 7.08 5 6 2O 1.4 O37-0615 OID F 3.75 1O 9 -10 1.65 O37-0711 OID F 4.75 1O 3 -70 3.48 O38-0046 OID M 5.17 7 3 -57.143 1.72 O40-0644 BID F 4.75 8 7 -12.5 1.06 O41-OO69 BID M 3.08 8 6 -25 1.3 O41-0098 OID M 2.35 8 3 -62.5 2.4 O41-0649 OID F 2.42 9 1O 1.111 4.75 O42-O105 BID M 9.17 8 8 O 2.09 O43-OO62 BID M 6 8 2 -75 O43-OO81 BID M 6 6 2 -66.667

0492. As described in Example 2, the mean 6B-maltrexol for the drug notated as either 1 or 2, respectively (in other plasma concentration in the oxycodone and naltrexone BID words, EC51 is not the concentration having 51% of the group was Statistically different from that in the oxycodone maximal effect, but rather EC51 is the concentration having and naltrexone QID group (p<0.001). There was also a a particular potency (e.g. 50% of the maximal effect for significant difference between the BID group and the QID Effect No. 1); the respective values for C are the concen group in pain intensity reduction, with the BID group trations of drugs notated as 1 or 2, and the values of n1, and experiencing a significant reduction in pain intensity. It was n2 that correspond to the Sigmoidicity factors that are unexpected that the QID group and BID group would differ asSociated with particular EC values. In the Emax composite in this manner. The plasma concentrations of 6B-maltrexol model, "+" is used to indicate absolute values, Sometimes it appear to be at Steady State at the conclusion of each dosing is shown as a "- which reflects a negative Second term. interval. (See FIG. 7). Therefore, in addition to the above 0495. The Emax composite model is a recognized com dose group differences, the plasma concentration-effect rela posite model for PK/PD data analysis set forth, for example, tionship between 6B-naltrexol concentrations and clinical in Gabrielsson et al., PHARMACOKINETIC/PHARMA outcomes (effects) can be observed, with lower Steady State CODYNAMIC DATA ANALYSIS: CONCEPTS AND plasma concentrations of 6f-naltrexol corresponding to APPLICATIONS, pp. 191-193 and 801-808 (2000), and the greater clinical efficacy (e.g., percent change in pain inten computer command files provided with the reference and sity). described, including with examples of the computer print 0493 FIGS. 11 and 12 illustrate this plasma concentra outs on pages 801-808, all of which is incorporated by tion-effect relationship. FIG. 11 plots the percent change in reference herein. However, it is believed that the Emax pain intensity reported by the subjects in Table 25 (y-axis) composite model has not previously been utilized for the VS. 6(3-maltrexol plasma concentrations measured for those analysis of PK data from administering low doses of opioid subjects (X-axis). FIG. 11 includes data from Subjects antagonists Such as naltrexone for enhancing the potency of receiving the BID dosing regimen of the combination drug opioid agonists Such as Oxycodone, as described herein. and Subjects receiving the QID dosing regimen of the From the plasma concentration-effect data obtained in this combination drug. The data as plotted in FIG. 11 describe a Example, it is contemplated that the opioid antagonist, at U shaped plasma concentration-effect relationship. FIG. 12 lower plasma concentrations, is impacting the total effect plots the percent change in pain intensity reported by the (percent change in pain intensity), primarily as described by Subjects receiving the BID dosing regimen of the combina the terms of the equation denoted with a 2. tion drug VS. 6B-maltrexol plasma concentrations measured 0496 The recognition of the applicability and utility of a for those Subjects. composite model as shown above enables the Selection of preferred and/or Suitable ranges for the combined use of an 0494 For the first time, the plasma concentration-effect opioid antagonist with an opioid agonist as described herein. relationship of low dose of an opioid antagonist when The composite model provides the relative contribution of administered with an opioid agonist has been represented by an opioid antagonist with respect to enhancing pain relief, the Emax composite model: for example, as measured by a reduction in pain intensity. The effective percentage decrease in pain intensity, E, has EC52n2+Con? been found to be described by a relatively wide scope of where the respective Emax values represent maximum effect preferred plasma concentrations by the Emax composite for a given drug, EC51 and EC52 represent the potencies, model, as shown in the data and Figures described herein. US 2006/0009478 A1 Jan. 12, 2006 64

0497. The plasma concentration-effect data were fit to the Emax composite model using the Software program TABLE 27-continued WinNonlin(R(commercially available from Pharsight Cor poration of Mountain View, Calif.) and the command files Parameters based on BID data developed by Gabrielsson et al. The plasma concentration Parameter Estimate effect data represented as circles in FIG. 11 were evaluated EC51 14.0 pg/ml mathematically and the plasma concentration-effect curve N1 (sigmoidicity 0.941 units/pg/ml shown in FIG. 11 was determined by the program and factor) command files. Similarly, the program and command files Emax2 76.3 units were used to determine the plasma concentration-effect EC52 0.422 pg/ml curve shown in FIG. 12 based on the data represented as N2 (sigmoidicity 2.16 units/pg/ml circles in FIG. 12. factor) 0498. The computer output (printout) of this process included EC51 and EC52 parameters, as well as parameters 0501 AS mentioned above, the BID dosing regimen of reflecting Statistical evaluation of the data, Such as coeffi the combination drug comprising naltrexone and oxycodone cient of variation (CV%). A variety of values, for example resulted in Statistically significant decreases in pain inten EC20 and EC90 (the concentrations at which 20% and 90%, sity. The Emax composite model provided the value of a respectively, of the maximum effect are obtained), may also EC52 plasma concentration of 63-maltrexol based on that be determined using the output from the WinNonlin(R) pro BID dosing regimen. Substantially the same EC52 result gram and Gabrielsson et all command files (or similar was obtained from the analysis of the total data Set (com programs and command files). Other values, for example prising data from both the BID and QID dosing regimens). ECO and EC100 and all values in between, also may be The fact that substantially the same EC52 result was determined graphically and/or using the values of N1 and obtained from the different data Sets Supports the Strength of N2 that correspond to the Sigmoidicity factors. the Emax composite model for analysis of the data. It also 0499 Table 26 shows parameters based on the curve Supports the use of the Emax composite model in order to shown in FIG. 11. These parameters are based on the data Select desirable doses of naltrexone (or another opioid for 6 B-maltrexol plasma concentrations and reduction in pain antagonist) in combination with oxycodone. from baseline pain intensity to final pain intensity from all 0502 Tables 26 and 27 illustrate the use of the total set Subjects for whom plasma concentration data was obtained of clinical data and the Subset associated with positive as described herein. These parameters are based on data clinical results in the same Emax composite model to from Subjects receiving the BID dosing regimens and Sub provide two sets of parameters. Either or both of the two sets jects receiving the QID dosing regimen. Estimate refers to of parameters can be used to identify plasma concentrations the value estimated by the WinNonlin(R) program and com having a probability of attaining a desired reduction of pain mand file for relating plasma concentrations to the pharma intensity or other efficacy outcome (e.g., pharmacodynamic codynamic effects Such as percent reduction in pain inten outcome) as described herein. From the plasma concentra sity. Convergence of the model was easily achieved and the tion-effect data and the Emax composite model, one can power of the condition number was acceptable. better assess what plasma concentrations of 63-maltrexol provide desired reduction in pain intensity and, more gen TABLE 26 erally, better pain treatment. Based on plasma concentration data (e.g., as shown in Table 25), presently preferred dosage Parameters based on Total (BID and QID) data forms for oral administration to a human Subject comprise a Parameter Estimate dose amount of opioid antagonist that is based on a Selected Emax1 26.8 units plasma concentration. Thus, naltrexone and/or 6 B-maltrexol EC51 14.4 pg/ml may be used to titrate a Subject to the appropriate dose for N1 (sigmoidicity factor) 0.907 units/pg/ml that Subject thus providing a convenient means for individu Emax2 79.7 units alized dosing. EC52 0.439 pg/ml N2 (sigmoidicity factor) 2.28 units/pg/ml 0503) The Emax composite model can facilitate dose titration for a human subject. Dose titration refers to the process of employing different doses (usually escalating 0500 Table 27 shows parameters based on the curve doses) in a Subject until a dose effective to achieve a desired shown in FIG. 12. These parameters are based on the data clinical outcome is found. Dose titration for the administra (6f-naltrexol plasma concentrations and percent reduction tion of an opioid antagonist and/or an opioid agonist accord in pain intensity) for Subjects receiving BID dosing regi ing to the present disclosure may be facilitated by using mens. Convergence of the model was easily achieved and plasma concentrations of 63-maltrexol, naltrexone, or the power of the condition number was acceptable. another marker of opioid antagonist. Dose titration may also be facilitated by using plasma concentrations of Oxycodone, TABLE 27 Oxymorphone, or another marker of opioid agonist may be used alone or in combination with a marker of opioid Parameters based on BID data antagonist for dose titration. Parameter Estimate 0504 For dose titration of the administration of an opioid Emax1 27.0 units antagonist and an opioid agonist to a human Subject, the Subject's plasma concentration of 63-maltrexol, naltrexone US 2006/0009478 A1 Jan. 12, 2006

or another marker for opioid antagonist is analyzed, and one eXOne plasma concentration of about /10 of the given 6f-nal or more clinical outcomes (Such as reduction in pain inten trexol plasma concentration is also contemplated. sity) for the Subject are analyzed. If a desired clinical outcome is not achieved (for example, if pain intensity is not 0509. The plasma concentration of 63-maltrexol at steady reduced to a desired level), the administration of opioid State is generally proportional to the dose amount of naltr antagonist and/or opioid agonist to the Subject is adjusted. eXOne in a BID dosing regimen. It has been found that a dose The composite model can be used to facilitate adjusting, or of an opioid antagonist Such as naltrexone given as a BID facilitate the decision to adjust, the administration of (a) the regimen that produces plasma concentrations of free 6?-nal opioid antagonist or (b) the opioid agonist or (c) both. trexol that are related by a proportionality factor to naltrex one correlated for a given dose of an opioid agonist Statis 0505. In the present method of titrating a human subject, tically (p<0.001) with percent decreases in pain intensity if a clinical outcome is not at a desired level, the plasma from base line for moderate to Severe pain. concentration of 6B-maltrexol is analyzed. If the 6-finaltrexol plasma concentration is not at a desired level, then admin 0510. Accordingly, a desirable dose amount of opioid istration of the opioid antagonist to the Subject is adjusted. antagonist, and optionally a desirable dose amount of opioid The administration of the opioid antagonist may be adjusted agonist, can be Selected based on a steady State plasma by adjusting the dose amount and/or dosing regimen. How concentration that exhibits a desired pharmacodynamic (PD) ever, if the 6f-naltrexol plasma concentration is already at a effect. Exemplary data for plasma concentrations and PD desired level, yet the clinical outcome is not at a desired effects are shown in Table 25. Based on the proportional level, then the administration of the opioid agonist to the relationship between concentration and dose, a formula for Subject is adjusted. The administration of the opioid agonist converting between concentration and dose can be estab may be adjusted by adjusting the dose amount and/or dosing lished by experimentally determining plasma concentrations regimen. that result from known dose amounts. This formula may be used to Select dose amounts of opioid antagonists converted 0506 For example, in a method of titrating the adminis from plasma concentrations showing a desired PD effect. tration of an opioid agonist and an opioid antagonist a Furthermore, the dose of a co-administered opioid agonist human Subject to reduce pain intensity in the Subject, if the may be adjusted, by increasing or decreasing the dose, reduction in pain intensity is not at a desired level, the relative to the opioid antagonist, to further optimize pain plasma concentration of 63-maltrexol is analyzed. If the relief or other efficacy outcomes as described herein. 6?-maltrexol plasma concentration is below a desired level, then administration of the opioid antagonist to the Subject is 0511. This linear relationship is true for the case where adjusted So that more opioid antagonist is administered to the daily dosing regimen results in a steady State plasma the Subject. If the 6f-naltrexol plasma concentration is concentration. In the present Example, the greatest fre above a desired level, then administration of the opioid quency of obtaining plasma concentrations associated with antagonist to the Subject is adjusted So that leSS opioid Significant improvement in pain relief as reflected by the antagonist is administered to the Subject. However, if the percentage change in the pain intensity Score was obtained 6f-naltrexol plasma concentration is already at a desired for the dose of naltrexone given BID. Naltrexone at the dose level, yet the reduction in pain intensity is not at a desired as described herein when given more frequently than BID level, then the administration of the opioid agonist to the resulted in a greater proportion of 63-maltrexol concentra Subject is adjusted So that more opioid agonist is adminis tions increasing above those for the BID dosing regimen in tered to the Subject. a statistically significant (p<0.0001) proportion of the popu lation. Stated differently, the plasma levels of naltrexone, as 0507 The Emax composite model may be used to iden measured by its major metabolite 6B-natrexol were too high tify desired levels of the plasma concentration of opioid in the OID dosing regimen, thus a Statistically significant antagonist, for example a level indicated by the composite increase in pain relief with the QID dosing regimen of model as having a desired level of efficacy. For example, naltrexone as described herein was not achieved. However, parameters, including but not limited to EC20, EC50 and Since individual patients in the QID dosing group did not EC90, identified by the composite model may be employed achieve an increase in pain relief as shown in Table 25, a to Select desirable levels of plasma concentrations of opioid Statistically Significant increase in pain relief with a similar antagonist (as measured directly or via a Surrogate marker QID dosage regimen of the opioid antagonist (e.g., naltrex Such as 6f-naltrexol). one) may be achieved when the dose of the opioid agonist (e.g., oxycodone) is increased relative to the amount of 0508 Parameters provided by the composite model may antagonist. be employed to select desirable doses of naltrexone from the plasma concentrations of 63-maltrexol, based on the forego 0512 Parameters, including but not limited to EC20, ing data, parameters and adjustments relating to 6f-naltr EC50 and EC90, identified by the composite model may be exol. AS mentioned above, when naltrexone is administered employed to Select desirable amounts of opioid antagonist in to a human Subject, the plasma concentration of 6B-maltrexol various dosage forms. A desired amount of opioid antagonist is useful as an indicator of the absorption of naltrexone, can be determined from a Selected plasma concentration Since 6?-naltrexol is generally present in plasma at concen arising from a known amount of opioid antagonist, Since the trations much higher than those of naltrexone due to the relationship between concentration and dose amount is rapid metabolism of naltrexone to yield 63-maltrexol. For generally linearly proportional. The plasma concentrations example, a 63-maltrexol plasma concentration of about 0.4 of 63 naltrexol from randomly selected samples from Sub tug/ml indicates a naltrexone plasma concentration of about jects receiving 1 lug of naltrexone and 20 mg of oxycodone 0.04 ug/ml in the plasma Sample, and where a given 60B in a BID dosing regimen were fit to the Emax composite naltrexol plasma concentration is provided herein, a naltr model. The EC52 of 63 maltrexol in the plasma, as the US 2006/0009478 A1 Jan. 12, 2006 66

Surrogate marker for the active drug naltrexone in the Where the BID dosing regimen comprises other amounts of plasma, corresponding to 1 lug of naltrexone from the BID Oxycodone per dose, exemplary dose amounts of opioid dosing regimen was computed. antagonist are contemplated: 1 mg oxycodone per dose: from about 0.041 ug to about 0.119 ug opioid antagonist per 0513. By way of example, but not as a limitation, param dose 2.5 mg oxycodone per dose: from about 0.103 ug to eters provided by a composite model are useful for predict about 0.297 ug opioid antagonist per dose 5 mg oxycodone ing doses from desirable lower levels of plasma concentra per dose: from about 0.207 ug to about 0.593 ug opioid tions of 6p–naltrexol. More particularly, the EC52 parameter antagonist per dose 10 mg oxycodone per dose: from about in Table 26 Suggests that a 6f-naltrexol plasma concentra 0.415 lug to about 1.19 ugs opioid antagonist per dose 40 mg tion of about 0.439 tug/ml or more may be employed to attain Oxycodone per dose: from about 1.66 ugs to about 4.74 ugs better than a 50% reduction in pain intensity. Additional opioid antagonist per dose 80 mg oxycodone per dose: from preferences may be Selected; for example, if one wishes to about 3.32 ugs to about 9.48 ugs opioid antagonist per dose attain better than 20% or better than 90% reduction in pain 160 mg oxycodone per dose: from about 6.64 ugs to about intensity, one may Select the plasma concentrations indi 18.96 ugs opioid antagonist per dose Thus, for a BID dosing cated in FIG. 11 that correspond to the 20% or the 90% regimen that includes an amount of oxycodone, presently effectiveness levels, respectively. preferred dose amounts of opioid antagonist may comprise 0514 AS another example, but not as a limitation, param from about 0.041 ug to about 18.96 ugs. eters provided by the composite model are useful for Select ing desirable higher levels of plasma concentrations of 0518. As another example, the plasma concentration 6f-naltrexol. AS one avenue, the EC51 parameter may be effect data in Table 26, which relate to the total plasma used in a fashion similar to the use of the EC52 parameter concentration-effect data from subjects receiving the BID as described above. dosing regimen and Subject receiving the QID dosing regi men, and the mathematical evaluation of the data using the 0515 A range of preferred dose amounts was calculated composite Emax/Imax model, as exemplified in FIG. 11, from the Emax composite model using EC20 derived from may be employed to Select preferred dose amounts of opioid the graphic output and the sum of the EC52 plus the CV% antagonist more generally. For a dosing regimen that obtained from the model. For example, a range of dose includes 20 mg oxycodone, presently preferred dose amounts is Selected wherein the low point is the dose amount amounts of opioid antagonist comprise from about 0.830 ug corresponding to the plasma concentration at EC20, and the to about 5.02 ugs. Where the dosing regimen comprises high point is the dose amount corresponding to the plasma other amounts of oxycodone per dose, exemplary dose concentration that is the sum of the EC52 plus the CV (% amounts of opioid antagonist are contemplated: (133) obtained from the Emax composite model. By way of example, but not as a limitation, where the opioid antagonist 0519) 1 mg oxycodone per dose: from about 0.041 ug to naltrexone is provided in a dosing regimen that also includes about 0.252 ug opioid antagonist per dose 2.5 mg oxycodone 20 mg oxycodone, preferred dose amounts of opioid antago per dose: from about 0.104 ug to about 0.63 ug opioid nist may comprise the range of from about 0.829 ug to about antagonist per dose 5 mg oxycodone per dose: from about 2.37 lugs. 0.208 ug to about 1.26 ug opioid antagonist per dose 10 mg Oxycodone per dose: from about 0.415 lug to about 2.51 ugs 0516 For a given opioid agonist that may be given in opioid antagonist per dose 40 mg oxycodone per dose: from different dose amounts, it may be desirable to provide about 1.66 ugs to about 10.0 ugs opioid antagonist per dose preferred concentrations or amounts of opioid antagonist. If 80 mg oxycodone per dose: from about 3.32 ugs to about the dosing regimen is to include 10 mg oxycodone (rather 20.1 lugs opioid antagonist per dose 160 mg oxycodone per than 20 mg), an alternative preferred dose amounts may dose: from about 6.64 ugs to about 40.2 ligS opioid antago comprise the range of from about 0.415 lug to about 1.19 ugs. nist per dose Thus, for a BID dosing regimen that includes It is contemplated that, generally, a preferred dose amount an amount of oxycodone, presently preferred dose amounts may be adjusted in a proportionate manner to a change in of opioid antagonist may comprise from about 0.041 ug to Oxycodone amount. If oxycodone amount is reduced or about 40.2 lugs. increased by a factor of 2, 4, or 8 (or other factor), the end points of the preferred range are each reduced or increased 0520) Furthermore, any of the foregoing ranges may be by a same factor (2, 4, or 8 or other factor)). broadened by Substituting the foregoing lower ends with a lower end of about 0.0002 tug since dose amounts as low as 0517. Accordingly, the plasma concentration-effect data about 0.0002 ug are presently contemplated. It was observed set forth above for the subjects receiving the BID dosing that the lower end of the ranges can approach Zero based on regimen or the total plasma concentration-effect data (BID the relatively low CV % S observed at the low end of the and QID) dosing regimens) can be employed to Select dose composite model (i.e., the values 132 and 151 for the BID amounts of opioid antagonist to be administered. For and total (BID and QID) data sets, respectively). This example, the plasma concentration-effect data in Table 27, indicates that even lower dose amounts of naltrexone and which relate to the plasma concentration-effect data from other opioid antagonists would be expected to be active, and Subjects receiving the BID dosing regimen, and the math dose amounts of about 0.0002 tug would be expected to be ematical evaluation of the data using the Emax composite active albeit in a decreasing proportion of the population. model, as exemplified in FIG. 12, may be employed to Select dose amounts of opioid antagonist to be administered 0521. The present Example also provides preferred meth in a BID dosing regimen. Employing that data and the ods and materials comprising opioid antagonists other than composite model, for a BID dosing regimen that includes 20 naltrexone, Such as naloxone and nalmefene. It is believed mg oxycodone, presently preferred dose amounts of opioid that, generally, the preferred dose amounts of naltrexone antagonist comprise from about 0.829 ug to about 2.37 lugs. calculated above are useful for other opioid antagonists. US 2006/0009478 A1 Jan. 12, 2006 67

Persons skilled in the field will recognize a particular opioid Step (c), and (e) adjusting the amount of the opioid agonist antagonist may have potency, bioavailability, metabolism, if one or more of the assessed Symptoms or Signs are not clearance, or other characteristics that Suggest an adjustment alleviated to a desired extent. to the dose amount, dosage form, or dosing regimen. For 0525) In the titration methods and materials provided example, for opioid antagonists having reduce oral avail herein, it may be desirable to repeatedly administer the ability compared to naltrexone, it is contemplated that a opioid antagonist Such that a steady State is achieved before higher oral dose amount will be provided, or that a more assessing one or more Symptoms or signs of an arthritic frequent dosing regimen will be employed, or that an condition, inflammation associated with a chronic condition, intravenous dose will be provided, or Some other adjustment or chronic pain. The initial Step of administering a first will be made. Such adjustments are well within the ability of amount of an opioid antagonist and/or a first amount an persons skill in the field. opioid agonist can be repeated if the measured plasma 0522. As discussed above, methods and materials are concentration is within the predetermined plasma concen provided for titrating an opioid antagonist administered to a tration range and/or if the assessed symptom(s) or sign(s) is human Subject. By way of example, but not as a limitation, alleviated to a desired extent. a Suitable method comprises the steps of (a) administering 0526 In the titration methods and materials provided an amount of an opioid antagonist and an amount of an herein, it is contemplated that one or more of the assessed opioid agonist to the Subject, (b) measuring a plasma con Symptoms or Signs may be pain, Stiffness, and/or difficulty in centration in the Subject of the opioid antagonist or a physical function had by the Subject, or measures of pain, Surrogate of the opioid antagonist, and (c) adjusting the StiffneSS and difficulty in physical function, Such as the amount of the opioid antagonist administered to the Subject measures set forth in the WOMAC Osteoarthritis Index or if the measured plasma concentration is outside a predeter one of its SubScales. For example, a Symptom or sign mined plasma concentration range. The predetermined assessed for purposes of titration may be pain as measured plasma concentration range can be from concentrations as pain intensity. The pain intensity measurement may be predicted by a model of plasma concentration-effect rela attenuated as compared to a pain intensity baseline mea tionship (e.g., the Emax composite model described above). Surement of the Subject. For example, the pain intensity The predetermined plasma concentration range can be the measurement may be reduced by at least about 20%, alter range predicted by the model to provide a reduction in pain natively at least about 50%, alternatively at least about 90%, intensity of about 20% or greater, alternatively about 50% or compared to a pain intensity baseline measurement of the greater, alternatively about 90% or greater. The predeter Subject. mined plasma concentration can be based on the plasma concentration-effect model shown in FIG. 11 or FIG. 12. 0527. In the titration methods and materials provided herein, it is contemplated that a plasma concentration of the 0523 However, the present methods and materials for opioid antagonist or a Surrogate of the opioid antagonist may titrating an opioid antagonist administered to a human Subject are not limited to the use of a composite model or to be measured, and the amount of the opioid antagonist can be the use of predetermined plasma concentrations. By way of adjusted based in part on the measured plasma concentra example, methods and materials of titrating an opioid tion. For example, the amount of the opioid antagonist antagonist administered to a human Subject are provided, administered to the Subject is increased if the measured which comprise (a) administering an amount of an opioid plasma concentration is lower than a predetermined plasma antagonist and an amount of an opioid agonist to the Subject, concentration value. AS another example, the amount of the (b) assessing one or more Symptoms or signs of an arthritic opioid antagonist administered to the Subject is decreased in condition, inflammation associated with a chronic condition, the measured plasma concentration is higher than a prede or chronic pain, (c) measuring a plasma concentration in the termined plasma concentration value. As yet another Subject of the opioid antagonist or a Surrogate of the opioid example, the amount of the opioid antagonist administered antagonist, and (d) adjusting the amount of the opioid to the Subject is maintained in the measured plasma con antagonist or the amount of the opioid agonist to the Subject centration is within a predetermined plasma concentration based on the measured plasma concentration. Step (d) may range, and optionally the amount of the opioid agonist include comprises adjusting the amount of the opioid administered to the Subject is increased. antagonist administered to the Subject, alternatively or addi 0528 While the foregoing generally preferred concentra tionally, step (d) can comprises adjusting the amount of the tions and amounts of opioid antagonists are contemplated opioid agonist administered to the Subject. for use with a wide variety of opioid agonists, it is contem plated that, for particular opioid agonists, particular concen 0524. As another example, methods and materials of trations and/or amounts may be Selected based on the titrating an opioid antagonist administered to a human present disclosure. The foregoing generally preferred con Subject are provided, which comprise (a) administering an centrations and amounts have been Selected based on data amount of an opioid antagonist and an amount of an opioid from clinical Studies employing the opioid antagonist nal agonist to the Subject, (b) assessing one or more symptoms trexone and the opioid agonist oxycodone, however they are or Signs of an arthritic condition, inflammation associated also contemplated for use with a wide variety of opioid with a chronic condition, or chronic pain, and (c) adjusting antagonists and opioid agonists. the amount of the opioid antagonist administered to the Subject if one or more of the assessed Symptoms or Signs are not alleviated to a desired extent. Step (c) can also comprise EXAMPLE 4 maintaining the amount of the opioid agonist administered 0529. A clinical study was conducted as described in to the Subject. The method may also comprise the Steps of Example 1 (Part A) and data were obtained as described in (d) re-assessing one or more of the Symptoms or signs after Examples 1 and 2. Plasma Samples from Selected Subjects in US 2006/0009478 A1 Jan. 12, 2006 68 the clinical Study were used to assay for the presence and aliquots at different dilutions. Two dilutions (1 in 1 and 1 in concentration of Selected cytokines. 10) of each Sample were assayed on two separate human Th1/Th2 cytokine canvases. In order to quantify the cytok 0530 Plasma samples were analyzed using a commercial ine concentrations, Standard curves were generated for each cytokine assay from Pointilliste (www.pointilliste.com) to dilution. A mixture of 9 cytokines was run on each of the quantify the concentrations of IL2, IL4, IL5, IL6, IL10, canvases and used to calculate a Standard curve, which was IL13, GM-CSF, interferon and TNFC. Plasma samples were used to determine the amount of each cytokine in the Separately analyzed for IL1C..and IL1B, which were quanti Samples. The Standard curves were plotted with the Signal tated using a conventional cytokine assay by Pointilliste. intensity as a function of the cytokine concentration in The cytokine assay for the quantitation of IL2, IL4, IL5, IL6, ng/ml. A CCD camera was used with Pointilliste's Canvas IL10, IL13, GM-CSF, interferon and TNFC. employed, Analysis Tools Software to generate data corresponding to Pointilliste's Human Th1/Th2 Cytokine Canvas product which contains binding Sites for each of these nine cytok cytokine concentrations. ines. The array pattern of cytokine antibodies printed in each 0533. In addition to the assays using the Pointilliste well of a 96 well microtiter plate is shown in Table 28. Human Th1/Th2 Cytokine Canvas, conventional ELISA analysis was used to measure the concentrations of IL1C..and TABLE 28 IL1B in the plasma samples. The standard curves for IL1C. and IL1B were also plotted with the Signal intensity as a Pattern of Human Th1/Th2 Cytokine Canvas function of the cytokine concentration in ng/ml. Alignment Anti-IL2 Anti-IL2 Anti-IL13 Anti-IL13 0534 Tables 29 through 31 show measurements of cytok marker Negative Anti-IL4 Anti-IL4 Anti-GM- Anti-GM ine concentrations (ng/ml) obtained as described herein and control CSF CSF data calculated from those measured concentrations. In Negative Anti-IL5 Anti-IL5 Anti-IFNY Anti-IFNY Tables 29 through 31, the following abbreviations are used: control “OXY' refers to the treatment group receiving oxycodone Reagent Anti-IL6 Anti-IL6 Anti-TNFC. Anti-TNFC. Control 1 QID as described in Example 1; “BID” refers to the treat Reagent Anti-IL10 Anti-IL10 Negative Alignment ment group receiving the combination drug of oxycodone Control 2 control marker and naltrexone BID as described in Example 1; “QID” refers to the treatment group receiving the combination drug of Oxycodone and naltrexone QID as described in Example 1, Two measurements (duplicates) for each cytokine were “GM' refers to granulocyte/macrophage colony Stimulating possible for each plasma Sample applied to a canvas, Since factor; “IFN" refers to interferon gamma; “TNF" refers to the canvas has two binding sites for each cytokine. tumor necrosis factor alpha; “IL2” refers to interleukin 2; “IL4” refers to interleukin 4; “IL5” refers to interleukin 5; 0531 Fifty-seven frozen human plasma samples contain “IL6” refers to interleukin 6; “IL10” refers to interleukin 10; ing EDTA as an anticoagulant were thawed on ice and and “IL13’ refers to interleukin 13. transferred to a Sterile 96-deep well polypropylene plate. The plate was centrifuged briefly at 4 C. to clarify the 0535 Table 29 shows the individual cytokine measure plasma. Aliquots of clarified plasma were removed for ments obtained from each Sample as identified by Sample cytokine analysis, and the remaining Samples in the 96-deep identification number. Accordingly, Table 29 shows all the cytokine measurements that were obtained for each Sample. well polypropylene plate were stored at -80 C. Table 30 shows a compilation of the individual cytokine 0532. The aliquots of clarified plasma were transferred to measurements obtained from the plasma Samples. These Sterile non-protein binding 96-well polypropylene plates to measurements were used to determine the mean cytokine enable parallel processing of the Samples. Each of the Wells concentrations. The numbers of measurements for the Vari of these plates included a Pointilliste Human Th1/Th2 ous cytokines differ because different interferences affected Cytokine Canvas as shown in Table 26. Two different 96 Samples and cytokine measurement within those Samples well plates were used, and each received a Subsample of the differently.

TABLE 29 Individual Cytokine Concentrations (ng/ml) Requisition # IL2 IL2 IL4 IL4 IL5 IL5

21896.190 O.20055269 O.11856273 21.896054 2298.2837 O.O9166477 O.O763O626 21366538 0.2226875 O1560676 2O889685 O.15974633 O.15681396 2O468981. O.26894.192 O.16131945 2087.1516 O.36578316 O15581297 209966.62 2O322246 O.7233O313 O.SS323963 O.26509831 O.2369057 2O893O86 O.17732O26 O.O8939692 2O904434

2098.2936

US 2006/0009478 A1 Jan. 12, 2006 72

TABLE 30-continued -continued Cytokine Concentration Measurements Obtained from IFN IFN IFN Plasma Samples from Clinical Study Cytokine Values O.O722552 O.O697.5249 O.O7442144 O.O786032 OXY BID QID 0.2197O779 O.127908O8 0.24065142 O.134595.54 O.2443O29 O.O.722552 O.O697.5249 O.291.3878 O.O7442144 O.O786O32 0.2197O779 O.127908O8 TNF TNF TNF 0.24065142 O.134595.54 O.2443O29 O.O53116 O.04704521 O.O562124 O.291.3878 O.O5315699 0.0522O257 O.O6228325 O.O5331531 0.05482446 O.1O294933 TNF TNF TNF O.O6095267 O.O5611.238 O.14351714 O.14688815 0.05757872 O.156946.53 O.O53116 O.04704521 O.O562124 O.2OOO4415 0.05856579 O.16723OO2 O.O5315699 0.0522O257 O.O6228325 O.5152O632 O.O611985 O.2690876 O.O5331531 0.05482446 O.1029.4933 O.O6095267 O.O5611238 O.14351714 O.51531889 O.O6890438 0.27045659 O.14688815 0.05757872 O.156946.53 O.O695864 O35271469 O.2OOO4415 0.05.856579 O.16723OO2 0.073890.75 0.37967O17 O.5152O632 O.O611985 O.2690876 O.O79884.09 O.3832746 O.51531889 O.O6890438 0.27045659 O.O855576 O42359.475 O.O695864 O.35271469 O.12529.323 0.07389075 0.37967O17 O.13392,305 O.O798.84.09 O.3832746 0.0855576 O.423594.75 O.125293.23 O.13392305 0538 AS indicated by the missing values in Table 29 and the different number of measurements in Table 30 for the various cytokines, the cytokine assay did not provide mea 0537) Surements of all nine cytokines for each Sample. Many cytokine measurements were not obtained due to one or more interferences with the detection mechanism of the assay. The missing values are attributed to random occur IL13 IL13 IL13 rences of high background, exceSS heme, lipolysis, desicca 2O7889.414 O.46117658 O.71O59496 tion, and the lowest level of quantification (LLOQ) for IL1. 236158936 0.47053745 O.74330939 3.29071344 O.472OO768 O.77623126 However, the missing values for cytokine concentrations 3.392.291.84 O.48572734 134132334 occurred randomly among the Subjects, and the random 0.522.3157 1.75789523 occurrence of missing values is believed to not interfere with O.52753O84 1.774.26577 O.532O7364 4.31719746 the accumulation of data. Accordingly the measurements O.54685694 4.565.15688 which were obtained from the assay are believed to be O.633584O1 meaningful. O.70581467 0.73173353 O.81325,709 0539 Table 30 shows the differences in cytokine levels 1.3323OOF3 between the different treatment groups (OXY, BID and QID) 146693.423 1.75O183O2 in the clinical study. Table 31 the means for each treatment 180730556 group of the plasma concentrations of the various cytokines, along with the Standard deviation for the measurements GM GM GM within the treatment groups. The mean values for the cytok 0.53138737 O.2O236439 O.333784.08 ine concentrations detected for each plasma Sample analyzed O.6O2O3722 O.2O71141 O.37383059 from the various treatment groups is Set forth along with the O.66705429 O.233.66778 140590O28 O.67155886 O.26198O22 141686O33 Standard deviation. The mean and Standard deviation values were calculated using the duplicate values obtained from various plasma Samples. US 2006/0009478 A1 Jan. 12, 2006 73

TABLE 31 Mean of Cytokine Concentrations (ng/ml) from Random Sample of Subjects OXY BID OID OXY BID OID OXY BID QID IL2 IL2 IL2 IL4 IL4 IL4 IL5 IL5 IL5

N 14 14 14 N 8 4 8 N O O 2 Mean 0.503 0.12 0.721. Mean O.238 0.211 O.396 Mean O.487 Std Dev 0.54 0.119 0.667 Std Dev 0.156 0.043 0.2O3 Std Dev O.OO1

OXY BID OID OXY BID OID OXY BID QID IL6 IL6 IL6 IL10 IL10 IL10 IL13 IL13 IL13

N 14 18 2O N 1O 8 14 N 18 3O 22 Mean O.2 O.128 O.189 Mean 0.628 0.245 0.414 Mean O.876 0.559 0.917 Std Dev 0.194 0.087 0.123 Std Dew 0.52 0.188 0.652 Std Dev 1121 O.459 1.244

OXY BID OID OXY BID OID OXY BID QID GM GM GM IFN FN FN TNF TNF TNF

N 4 4 4 N 4 O 6 8 14 12 Mean O616 0.226 O.883 Mean O.152 O.158 Mean O.2 O.O73 O.231 Std Dev 0.066 0.027 0.611 Std Dev 0.091 O.O9 Std Dev 0.2-2 O.O26 O.132

0540. These data indicate that methods and materials as 0543. A constant weight series based on a common described herein for the treatment of arthritic conditions, formulation is followed in the manufacture of oxycodone inflammation associated with a chronic condition, and/or HCl/naltrexone HCl tablets, oxycodcone HCl tablets, and chronic pain, including pain in conjunction or associated placebo tablets. Differences in the mass of the active phar with arthritic conditions or inflammation, are useful to maceutical ingredient (API) in the various tablet dosage decrease the plasma concentration of various proinflamma strengths (in this case oxycodone) are compensated for by tory cytokines. These data also indicate that cytokines are adjusting the amount of lactose monohydrate to achieve a appropriate biomarkers, including for the monitoring, detec consistent mass among all active and placebo tablets. tion, diagnosis and/or treatment of arthritic conditions, inflammation associated with a chronic condition and/or 0544 The components, pharmaceutical grade, and func chronic pain. Such biomarkers are useful to detect anti tion of each component used to make oxycodone HCl/ inflammatory activity or other effects of the present methods maltrexone HCl tablets and oxycodone HCl tablets are and materials. Biomarkers, Such as cytokines, are of interest provided in Table 32 below. Except for the Opadry(R) film to the pharmaceutical industry for various uses, including, coatings, the components used in the tablet dosage forms are for example, to determine potential activity of drugs in clinical development. compendial in the current USP/NF. TABLE 32 EXAMPLE 5 0541 Solid oral dosage forms comprising opioid agonists Components for Oxycodone HCl/Naltrexone HCl Tablets and/or opioid antagonists can be prepared by a variety of and Oxycodone HCl Tablets processes well-known to those skilled in the art. For Component Function example, methods and materials as described in U.S. Patent Oxycodone HCl, USP Active pharmaceutical ingredient Application Publication No. 2003/0191147 (previously Naltrexone HCl, USP Active pharmaceutical ingredient incorporated by reference herein) and WO 01/85257 (PCT/ Lactose, Monohydrate, NF Diluent Hydroxypropyl Methylcellulose, USP Binder US01/14377) are useful in preparing dosage forms compris Citric Acid, Anhydrous, USP Acidifier for pH adjustment ing opioid agonists and/or opioid antagonists, including Sodium Hydroxide, NF Alkalizer for pH adjustment wherein the dosage form comprises amounts of opioid Low-Substituted Hydroxypropyl Disintegrant antagonists of 1 mg or less. AS another example, Solid oral Cellulose, NF Magnesium Stearate, NF Lubricant dosage forms comprising oxycodone hydrochloride (OXY) Talc, USP (Hydrous Magnesium Glidant and naltrexone hydrochloride (NTX) are prepared as Silicate) described herein. For clinical studies as described in Water** for Injection, USP Processing Solvent Example 1, tablets having different amounts of oxycodone Opadry (R) Clear Base Coat were manufactured, though the amount of naltrexone was Opadry (R) II Yellow Aesthetic Color Coat the same (0.001 mg) among the tablets of different strength. *Naltrexone HCl not present in Oxycodone HCl tablets. 0542 Tablet formulations containing oxycodone HCl at **Removed during processing various dose levels (2.5, 5, 7.5, 10, 15 and 20 mg/tablet) and low-dose naltrexone HCl (0.001 mg) were prepared. Four 0545. The following steps were used to prepare tablets matching active controls of oxycodone HCl tablets at Vari comprising oxycodone and naltrexone. These Steps as well ous strengths (2.5, 5, 7.5, and 10 mg/tablet) and a matching as in-process controls (IPC) are Summarized in the flowchart placebo tablet were also prepared. of FIG. 13. US 2006/0009478 A1 Jan. 12, 2006 74

0546. Oxycodone HCl, lactose monohydrate, low-substi tuted hydroxypropyl cellulose (Portion A), and hydroxypro TABLE 33-continued pyl methylcellulose (Portion A) were dry blended in a granulator. This dry material blend was granulated in a wet Oxycodone HCI 2.5 mg/Naltrexone HC 0.001 mg Tablets granulation Step with an aqueous Solution of naltrexone HCl, Quantity per Quantity per citric acid, and hydroxypropyl methylcellulose Solution (pH Component Tablet (mg) Batch (g) at 3.5) (Portion B). More water was added if needed to obtain a Satisfactory granulation. The wet granulation was Tablet Core Total 2OO.OO 66O.O Sieved in a wet sizing Step through a mesh Screen and dried Color Coating: in a fluidized bed to an endpoint moisture content of not Opadry Clear (Base Coat) 2.OO 6.6** more than 3 percent determined by a Loss on Drying (LOD) Opadry II Yellow (Aesthetic Color Coat) 8.00 26.4** measurement. Water for Injection, USP f 281.3* * 0547 The dried granulation was sieved through a mesh Screen in a dry Sieving Step. A portion of the dried granulate Coated Tablet Total 21O.OO 693.O approximately equal to the balance of formulation compo *For pH adjustment of granulation fluid to pH 3.5 + 0.2 nents was reserved. The remaining granulate was added to a **Theoretical quantities per batch are tabulated. An overage is prepared in manufacturing to compensate for processing losses (e.g., fluid retention in V-blender. transport lines and vessels, etc.). 0548. Each of the three components (low-substituted Removed during processing hydroxypropyl cellulose (Portion B), talc, and magnesium Stearate) were combined with an approximately equal por 0553 Table 34 sets forth the composition of exemplary 5 tion of the reserved dry granulation to form intermediate mg strength tablets (tablets comprising 5 mg oxycodone HCl mixtures. Each intermediate mixture was Sequentially added and 0.001 mg naltrexone hydrochloride). through a mesh Screen and into the V-blender. The granu lation was blended after each addition to achieve uniformity. TABLE 34 0549. The blended granulation was compressed into tab Qxycodone HCl 5 mg/Naltrexone HC 0.001 mg Tablets lets on a rotary tablet press. Tablets had a mean weight of Quantity per Quantity per about 200 mg. (approximate range 190 mg to 210 mg), mean Component Tablet (mg) Batch (g) hardness in the range of about 5 kp to 8 kp (approximate range 4 kp to 10 kp) and mean thickness of 4.3 to 4.7 mm. Tablet Core: Oxycodone HCl, USP S.OO 16.5 0550 Tablets were film coated in a perforated pan that Naltrexone HCl, USP O.OO1 O.OO33** included application of a clear base coating followed by an Lactose, Monohydrate, NF 167.30 552.1 aesthetic color coating. A commercially available clear coat Hydroxypropyl Methylcellulose, USP 2.82 9.3* * ing (Colorcon-Opadry Clear) was applied to achieve an Citric Acid, Anhydrous, USP 1.OO 3.3 average coating weight of 2+0.4 mg per tablet. A commer Sodium Hydroxide, NF q.s. to pH q.s. to pH Low-Substituted Hydroxypropyl 1688 55.7 cially available color coating (Colorcon-Opadry II Yellow) Cellulose, NF was applied to achieve an average coating weight of Magnesium Stearate, NF 1.OO 3.3 approximately 8-t1 mg per tablet. Talc, USP (Hydrous Magnesium Silicate) 6.OO 19.8 Water for Injection, USP f 73.7: * 0551. The amounts of active ingredients and excipients in various tablets of different strengths are set forth in Tables 33 Tablet Core Total 2OOOO 66O.O through 38. Color Coating: Opadry Clear (Base Coat) 2.OO 6.6** 0552 Table 33 sets forth the composition of exemplary Opadry II Yellow (Aesthetic Color Coat) 8.OO 26.4** 2.5 mg strength tablets (tablets comprising 2.5 mg oxyc Water for Injection, USP f 281.3* * odone HCl and 0.001 mg naltrexone hydrochloride). Coated Tablet Total 21O.OO 693.O TABLE 33 *For pH adjustment of granulation fluid to pH 3.5 + 0.2 **Theoretical quantities per batch are tabulated. An overage is prepared in Oxycodone HCI 2.5 mg/Naltrexone HC 0.001 mg Tablets manufacturing to compensate for processing losses (e.g., fluid retention in transport lines and vessels, etc.). Quantity per Quantity per Removed during processing Component Tablet (mg) Batch (g) Tablet Core: 0554 Table 35 sets forth the composition of exemplary 7.5 mg strength tablets (tablets comprising 7.5 mg oxyc Oxycodone HCl, USP 2.50 8.3 Naltrexone HCl, USP O.OO1 O.OO33** odone HCl and 0.001 mg naltrexone hydrochloride). Lactose, Monohydrate, NF 169.8O 560.3 Hydroxypropyl Methylcellulose, USP 2.82 9.3* * TABLE 35 Citric Acid, Anhydrous, USP 1.OO 3.3 Sodium Hydroxide, NF q.s. to pH q.s. to pH Oxycodone HCl 7.50 mg/Naltrexone HC 0.001 mg Tablets Low-Substituted Hydroxypropyl 16.88 55.7 Cellulose, NF Quantity per Quantity per Magnesium Stearate, NF 1.OO 3.3 Component Tablet (mg) Batch (g) Talc, USP (Hydrous Magnesium Silicate) 6.OO 19.8 Water for Injection, USP f 73.7: * Tablet Core: US 2006/0009478 A1 Jan. 12, 2006 75

HCl and 0.001 mg naltrexone hydrochloride). TABLE 35-continued TABLE 37 Oxycodone HCl 7.50 mg/Naltrexone HC 0.001 mg Tablets Oxycodone HCl 15 mg/Naltrexone HC 0.001 mg Tablets Quantity per Quantity per Component Tablet (mg) Batch (g) Quantity per Quantity per Component Tablet (mg) Batch (g) Oxycodone HCl, USP 7.50 24.8 Tablet Core: Naltrexone HCl, USP O.OO1 O.OO33** Lactose, Monohydrate, NF 1648O 543.8 Oxycodone HCl, USP 15.OO 49.5 Hydroxypropyl Methylcellulose, USP 2.82 9.3* * Naltrexone HCl, USP O.OO1 O.OO33** Citric Acid, Anhydrous, USP 1.OO 3.3 Lactose, Monohydrate, NF 157.30 519.1 Sodium Hydroxide, NF q.s. to pH q.s. to pH Hydroxypropyl Methylcellulose, USP 2.82 9.3* * Low-Substituted Hydroxypropyl 16.88 55.7 Citric Acid, Anhydrous, USP 1.OO 3.3 Cellulose, NF Sodium Hydroxide, NF q.s. to pH q.s. to pH Magnesium Stearate, NF 1.OO 3.3 Low-Substituted Hydroxypropyl 1688 55.7 Talc, USP (Hydrous Magnesium Silicate) 6.OO 19.8 Cellulose, NF Water for Injection, USP f 73.7: * Magnesium Stearate, NF 1.OO 3.3 Talc, USP (Hydrous Magnesium Silicate) 6.OO 19.8 Tablet Core Total 2OO.OO 66O.O Water for Injection, USP f 73.7: * Color Coating: Tablet Core Total 2OOOO 66O.O Opadry Clear (Base Coat) 2.OO 6.6** Color Coating: Opadry II Yellow (Aesthetic Color Coat) 8.OO 26.4** Water for Injection, USP f 281.3* * Opadry Clear (Base Coat) 2.OO 6.6** Opadry II Yellow (Aesthetic Color Coat) 8.OO 26.4** Coated Tablet Total 21O.OO 693.O Water for Injection, USP f 281.3* *

*For pH adjustment of granulation fluid to pH 3.5 + 0.2 Coated Tablet Total 21O.OO 693.O **Theoretical quantities per batch are tabulated. An overage is prepared in manufacturing to compensate for processing losses (e.g., fluid retention in *For pH adjustment of granulation fluid to pH 3.5 + 0.2 transport lines and vessels, etc.). **Theoretical quantities per batch are tabulated. An overage is prepared in Removed during processing manufacturing to compensate for processing losses (e.g., fluid retention in transport lines and vessels, etc.). 0555 Table 36 sets forth the composition of exemplary Removed during processing 10 mg strength tablets (tablets comprising 10 mg oxycodone HCl and 0.001 mg naltrexone hydrochloride). 0557. Table 38 sets forth the composition of exemplary 20 mg strength tablets (tablets comprising 20 mg oxycodone TABLE 36 HCl and 0.001 mg naltrexone hydrochloride).

Oxycodone HCl 10 mg/Naltrexone HC 0.001 mg Tablets TABLE 38 Quantity per Quantity per Component Tablet (mg) Batch (g) Oxycodone HCI 20 mg/Naltrexone HC 0.001 mg Tablets Tablet Core: Quantity per Quantity per Component Tablet (mg) Batch (g) Oxycodone HCl, USP 1O.OO 33.O Naltrexone HCl, USP O.OO1 O.OO33** Tablet Core: Lactose, Monohydrate, NF 162.30 535.6 Hydroxypropyl Methylcellulose, USP 2.82 9.3* * Oxycodone HCl, USP 2O.OO 66.O Citric Acid, Anhydrous, USP 1.OO 3.3 Naltrexone HCl, USP O.OO1 O.OO33** Sodium Hydroxide, NF q.s. to pH q.s. to pH Lactose, Monohydrate, NF 152.30 SO2.6 Low-Substituted Hydroxypropyl 16.88 55.7 Hydroxypropyl Methylcellulose, USP 2.82 9.3* * Cellulose, NF Citric Acid, Anhydrous, USP 1.OO 3.3 Magnesium Stearate, NF 1.OO 3.3 Sodium Hydroxide, NF q.s. to pH q.s. to pH Talc, USP (Hydrous Magnesium Silicate) 6.OO 19.8 Low-Substituted Hydroxypropyl 1688 55.7 Water for Injection, USP f 73.7: * Cellulose, NF Magnesium Stearate, NF 1.OO 3.3 Tablet Core Total 2OO.OO 66O.O Talc, USP (Hydrous Magnesium Silicate) 6.OO 19.8 Color Coating: Water for Injection, USP f 73.7: * Opadry Clear (Base Coat) 2.OO 6.6** Tablet Core Total 2OOOO 66O.O Opadry II Yellow (Aesthetic Color Coat) 8.OO 26.4** Color Coating: Water for Injection, USP f 281.3* * Opadry Clear (Base Coat) 2.OO 6.6** Coated Tablet Total 21O.OO 693.O Opadry II Yellow (Aesthetic Color Coat) 8.OO 26.4** Water for Injection, USP f 281.3* * *For pH adjustment of granulation fluid to pH 3.5 + 0.2 **Theoretical quantities per batch are tabulated. An overage is prepared in Coated Tablet Total 21O.OO 693.O manufacturing to compensate for processing losses (e.g., fluid retention in transport lines and vessels, etc.). *For pH adjustment of granulation fluid to pH 3.5 + 0.2 Removed during processing **Theoretical quantities per batch are tabulated. An overage is prepared in manufacturing to compensate for processing losses (e.g., fluid retention in transport lines and vessels, etc.). 0556 Table 37 sets forth the composition of exemplary Removed during processing 15 mg strength tablets (tablets comprising 15 mg oxycodone US 2006/0009478 A1 Jan. 12, 2006 76

0558 Clinical supplies of oxycodone HCl/naltrexone opioid antagonist naltrexone, including to evaluate BID and HCl tablets, oxycodone HCl tablets, or placebo tablets were QID dosing combinations of oxycodone and naltrexone, in packaged in plastic film blister packs with foil backing. The comparison to oxycodone alone and placebo. blister packs were placed inside a Sealed foil pouch with a 0562. A clinical study was designed to evaluate the Silica gel desiccant to assure that products conform to efficacy and/or Safety of oxycodone and naltrexone when Specifications while in use. compared to oxycodone alone, to evaluate the efficacy 0559) An advantage of dosage forms prepared as refer and/or Safety of oxycodone and naltrexone when compared enced and described in this example, including tablets made to placebo, to compare quality of life measures in patients by the procedure described above and Summarized in FIG. who received oxycodone and naltrexone to those who 13 is that undesirable binding of the opioid antagonist to the received oxycodone alone or placebo, to compare the dura excipients is essentially avoided. It was previously noted bility of analgesia of oxycodone and naltrexone compared to that Some opioid antagonists undesirably bind Significantly Oxycodone alone or to placebo, and/or to compare opioid to certain pharmaceutical excipients in an environment of withdrawal rates upon Study drug cessation in patients who use (see, e.g., WO 01/85257 (PCT/US01/14377) and U.S. received combinations and naltrexone to those who received Patent Application Publication No. 2003/0191147). Unde Oxycodone alone or placebo. Sirable binding generally causes an incomplete amount of the opioid antagonist to be released from a dosage form, 0563 A multicenter, randomized, double-blind, active within a particular time allotted for release in a dissolution and placebo-controlled Study was designed and conducted. test or in clinical use. For example, as described herein, the The Study evaluated the efficacy and/or Safety of exemplary use of an acidic pH during the wet granulating Step was oral formulations of oxycodone (OXY) and naltrexone advantageous with respect to avoiding undesirable binding. (NTX) compared to oxycodone (OXY) and placebo after a AS described above, the wet granulation Step employed a 1- to 6-week titration period with a 12-week fixed-dose granulation Solution having a pH adjusted to 3.5 with citric period in patients with moderate to Severe chronic low back acid. The tablets manufactured by this manufacturing pro pain. The study was designed to enroll a total of 700 cess did not exhibit undesirable binding of the opioid patients: 200 patients each in the oxycodone (OXY) and antagonist and the excipients to a significant degree. Accord naltrexone (NTX) BID, oxycodone (OXY) and naltrexone ingly, Some embodiments of the present methods and mate (NTX) QID and oxycodone (OXY) QID treatment groups, rials include Steps or excipients which reduce or minimize and 100 patients in the placebo group. undesirable binding of opioid antagonist and one or more 0564. At the screening visit, patients began a minimum pharmaceutical excipients, So that Such excipients do not 4-day washout period (maximum 10 days). During the bind the opioid antagonist to a significant degree in an washout period, patients Stopped taking all of their pain environment of use. medications other than acetaminophen (500 mg every 4-6 0560. While the invention will be described in connection hours PRN a maximum of 3000 mg/day). Adaily diary was with one or more embodiments, it will be understood that the to be utilized to record overall pain intensity (PI) and the invention is not limited to those embodiments. On the amount of acetaminophen taken each day. contrary, the invention includes all alternatives, modifica 0565 Patients who had taken a daily opioid dose equiva tion, and equivalents as may be included within the Spirit lent of oxycodone (>20 mg and s 160 mg) or tramadol >200 and Scope of the appended claims. mg during the previous week had an opioid taper. A daily opioid dose equivalent of oxycodone is readily calculated by EXAMPLE 6 those skilled in the art. For example, The Drug Conversion 0561. The effects of an opioid agonist and an opioid Calculator Version 2.0 on American Pain Society's website antagonist were evaluated in Subjects (e.g., patients) with (http://www.talaria.org/calculator J20.html) and/or the PDR back pain. A clinical Study was conducted in patients with Electronic Library, 2002) and/or Goodman and Gilman, moderate to Severe chronic low back pain using an exem supra (see, e.g., Tables 23.6 at page 606 of 10" Edition. An plary opioid agonist oxycodone alone or with an exemplary exemplary opioid conversion chart is shown in Table 39.

TABLE 39 Daily Quantity Daily Quantity Daily Oral Dose Opioid Content Equivalent to Equivalent to Equivalent to OXY 20; Per Unit of Oral OXY 20 mg/ Oral OXY 80 mg/ Opioid Compound 80; 160 mg/day US Brand Name Preparation day day Codeine Phosphate 120 mg; 480 mg., 960 mg Tylenol No. 3 30 mg/tablet 4 tablets 16 tablets Tylenol No. 4 60 mg/tablet 2 tablets 8 tablets Other codeine-containing combinations: Tylenol with Codeine Elixir, Phenergan w/Codeine syrup, Phenergan VC w/Codeine Syrup, Robitussin A-C syrup, Robitussin-DAC Syrup, Soma Compound w/ Codeine Tablets, Tussi-Organdin NR Liquid, Tussi-Organidin-SNR Liquid. Hydrocodone Bitartrate 20 mg. 80 mg. 160 mg Hycodan Syrup 5 mg/5 mL. 20 mL. 80 mL. Hycodan Tablet 5 mL/tablet 4 tablets 16 tablets Hycomine 5 mL/tablet 4 tablets 16 tablets Lortab 2.5/500 2.5 mg/tablet 8 tablets 32 tablets Lortab 5.0/500 5.0 mg/tablet 4 tablets 16 tablets Lortab 7.5/5OO 7.5 mg/tablet 2.5 tablets 10 tablets Lortab 10.5/500 10 mg/tablet 2 tablets 8 tablets US 2006/0009478 A1 Jan. 12, 2006 77

TABLE 39-continued Daily Quantity Daily Quantity Daily Oral Dose Opioid Content Equivalent to Equivalent to Equivalent to OXY 20; Per Unit of Oral OXY 20 mg/ Oral OXY 80 mg/ Opioid Compound 80; 160 mg/day US Brand Name Preparation day day Lortab Elixir 7.5 mg/15 mL 40 mL. 60 mL. Maxidone 10 mg/tablet 8 tablets Norco 5/325 5 mg/tablet S 6 tablets Norco 7.5/325 7.5 mg/tablet ets O tablets Norco 10/325 10 mg/tablet 8 tablets Tussionex 10 mg/5 mL 1. O 40 mL. Pennkinetic E-R Suspension Vicodin 5 mg/tablet Vicodin ES 7.5 mg/tablet 5 al ets Vcodin HP 10 mg/tablet Vicodin Tuss 5 mg/5 mL O Expectorant Vicoprofen 7.5 mg/tablet 5 al ets Zydone 5/400 5 mg/tablet al b Zydone 7.5/400 7.5 mg/tablet 5 al ets Zydone 10/400 10 mg/tablet Propoxyphene HCI 180 mg, 720 mg. Darvon Pulvule 65 mg/tablet . 1440 mg Darvon 65 mg/tablet 2 al b e S Compound 65 Propoxyphene Napsylate 300 mg: 1200 mg; 2400 mg Darvocet-N 50 50 mg/tablet Darvocet-N 100 100 mg/tablet Darwon-N 100 100 mg/tablet Oxycodone HCI 20 mg. 80 mg, 160 mg OxyContin 10 mg 10 mg/tablet OxyContin 20 mg 20 mg/tablet OxyContin 40 mg 40 mg/tablet Exceeds Dose OxyContin 80 mg 80 mg/tablet Exceeds Dose tablet OxyContin 160 mg 160 mg/tablet Exceeds Dose Exceeds Dose Limi OxyFast Oral 20 mg/mL 4 mL Conc Solution OxyIR Capsule 5 mg/capsule 6 capsules Percocet 2.5/325 2.5 mg/tablet 32 tablets Percocet 5.0/325 5.0 mg/tablet 6 tablets Percocet 7.5/500 7.5 mg/tablet O tablets Percocet 10/650 10 mg/tablet 8 tablets Percodan 5 mg/tablet 6 tablets Percolone 5 mg/tablet 6 tablets Roxicodone Oral 10 mg/10 mL 80 mL. Solution Roxicodone 15 15 mg/table 5 tablets (green) Roxicodone 30 30 mg/table Exceeds Dose 2 tablets (blue) Tylox 5 mg/capsule 16 tablets Meperidine HCl 300 mg: 1200 mg; 2400 mg Demerol Syrup 50 mg/5 mL 120 mL. Demoral 50 mg 50 mg/table 24 tablets Demoral 100 mg 100 mg/tablet 12 tablets Morphine Sulfate 20 mg. 80 mg, 160 mg Kadian 20 20 mg/table 4 tablets Kadian 20 30 mg/table Exceeds Dose 2 tablets

Kadian 20 50 mg/table Exceeds Dose 1.5 tablets

Kadian 20 60 mg/table Exceeds Dose 1 tablet

Kadian 100 100 mg/tablet Exceeds Dose Exceeds Dose Limi MS Contin 15 15 mg/table 5 tablets MS Contin 30 30 mg/table MS Contin 60 60 mg/table MS Contin 100, 100, 200 mg/ Exceeds Dose Exceeds Dose 2OO tablet Limi MS IR Oral 10 mg/5 mL 40 mL. Solution MS IR Oral 20 mg/5 mL 20 mL. Solution MS IR Oral 20 mg/5 mL 20 mL. Solution Conc. US 2006/0009478 A1 Jan. 12, 2006 78

TABLE 39-continued Daily Quantity Daily Quantity Daily Oral Dose Opioid Content Equivalent to Equivalent to Equivalent to OXY 20; Per Unit of Oral OXY 20 mg/ Oral OXY 80 mg/ Opioid Compound 80; 160 mg/day US Brand Name Preparation day day MSIR 15 15 mg/tablet 1 tablets 5 tablets/capsule or capsule MS IR 30 30 mg/tablet Exceeds Dose 2 tablets/capsule or capsule Limit Oramorph SR 15 mg/tablet 1 tablet 5 tablets ablet 15 Oramorph SR 30 mg/tablet Exceeds Dose 2.5 tablets ablet 30 Limit Oramorph SR 60 mg/tablet Exceeds Dose 1 tablet ablet 30 Limit Oramorph SR 100 mg/tablet Exceeds Dose Exceeds Dose ablet 100 Limit Limit Roxanol 100 100 mg/5 mL 1 mL 4 mL Conc Oral Solution Roxanol Conc 20 mg/mL 1 mL 4 mL Oral Solution Roxanol-T Oral 20 mg/mL 1 mL 4 mL Solution Methadone HCI 6.7 mg; 26.8 mg, 53.3 mg Dolophine HCl 5 5 mg 1 tablets 5 tablets Dolophine HCl 10 mg Exceeds Dose 2.5 tablets O Limit Levorphanol Tatrate 1.3 mg, 5.2 mg, 10.7 mg Levo-Dromoran 2 mg Exceeds Dose 2.5 tablets Limit Hydromorphone HCl 5 mg; 20 mg; 40 mg Dilaudid Oral 5 mg/5 mL. 1 mL 4 mL Liquid Dilaudid Rectal 3 mg/Supp 1 Supp 6 supp Supp Dilaudid 2 2 mg/tablet 2 tablets 10 tablets Dilaudid 4 4 mg/tablet 1 tablets 5 tablets (yellow) Dilaudid 8 8 mg/tablet Exceeds Dose 2.5 tablets (white) Limit Butorphanol tartrate 2 mg; 8 mg; 16 mg Stadol 1 mg/spray 2 sprays 8 sprays Pentazocine HCI 167 mg: 668 mg; 1336 mg Talacen 25 mg/caplet 6 caplets 24 caplets Talwin Nx 50 mg/caplet 3 caplets 12 caplets Fentanyl Duragesic 25 25 mcg?h Exceeds Dose 1 patch Limit Duragesic 50, 50, 75, 100 mcg/h Exceeds Dose Exceeds Dose 75, 100 Limit Limit

Reference: 1. Drug Conversion Calculator Version 2.0 on American Pain Society's website: http://www.talaria.org/calculatorJ20.html. 2. PDR Electronic Library, 2002.

0566 Patients were tapered off of their opioid or trama nence syndrome is a function of the half-life of the dol medication for a Sufficient amount of time to prevent opioid. With short half-life drugs such as morphine or withdrawal according to the investigator's clinical judg hydromorphone, the Symptoms may appear in 6-12 ment. If necessary, patients could take non-opioid analgesic hours and peak at 24-72 hours; with the long half-life medication during the opioid taper. drugs methadone and levorphanol, the Symptoms may 0567 A copy of the “Principles of Analgesic Use in the be delayed for Several days, and are typically less Treatment of Acute Pain and ', Fourth Edition, florid. The abstinence syndrome can be avoided by by the American Pain Society (APS) was provided as a slowly withdrawing chronically used opioid. Weaning reference for the taper procedure. The following is an a patient from opioids may proceed as follows: one-half excerpt from the booklet regarding physical dependence on of the previous daily dose may be given in q6 hr doses opioids and a guideline on the use of an opioid taper when for the first 2 days and reduced by 25% every 2 days. discontinuing opioids (page 33): This schedule is continued until a total daily dose of 30 mg/day of oral morphine in the adult is reached. After 0568 “Physical dependence is revealed in patients 2 days at this minimum dose, the analgesic may be taking chronic opioids when the abrupt discontinuation discontinued. An alternative withdrawal Schedule con of an opioid or the administration of an opioid antago Sists of Switching to oral methadone, using one-fourth nist produces an abstinence Syndrome. This Syndrome of the equianalgesic dose as the initial weaning dose is characterized by anxiety, irritability, chills alternating and proceeding as described above. Withdrawal Symp with hot flashes, Salivation, lacrimation, rhinorrhea, toms usually can be avoided by a slow opioid tapering diaphoresis, piloerection, nausea, vomiting, abdominal Schedule. Anxiety, tachycardia, Sweating, and other cramps, and insomnia. The time course of this absti autonomic Symptoms that persist may be lessened by US 2006/0009478 A1 Jan. 12, 2006 79

using transdermal clonidine (Catapress TTS) in a patch 0574. The demographics of the four groups was balanced size delivering 0.1-0.2 mg/day.” acroSS the groups as shown in Table 41. 0569. The rate of tapering in patients opioid medica tion(s) was to be no faster than the recommendation of the TABLE 41 APS guideline. The opioid taper schedule was to be tailored to the individual patient's Overall clinical condition and Oxycodone responses to optimize patient Safety. Methadone was not to and be used for the opioid taper due its long half-life and potential interference with the urine drug Screen at the Oxycodone Naltrexone Oxycodone and Baseline Visit. Placebo QID QID Naltrexone BID 0570. The following assessments were to be conducted prior to the taper: (1) written informed consent; (2) clinic ITT Population 101 2O6 2O6 2O6 pain intensity (PI); (3) review inclusion and exclusion Female 61.2% 61.7% 61.7% 61.5% criteria; (4) detailed medical history including concomitant Male 38.8% 38.3% 38.3% 38.5% medications taken one month prior to the Screening Visit; Age (Mean) 48.7% 47.9% 47.8% 48.0% (5) complete physical examination including height, weight Weight (kg) 84.4 85.4 90.1 85.6 and vital signs; and (6) EKG (QTc interval only). 0571 Upon completion of the opioid taper, the following assessments were to be conducted: (1) blood Samples for clinical laboratory tests (hematology tests, including hemo 0575 Of the 719 subject, 315 had opioid use within one globin, hematocrit, RBC, WBC, neutrophils, lymphocytes, month (30 days) of first dose of study medication: 43 in the monocytes, esoinophils, basophils and/or platelet count; placebo group, 99 in the oxycodone QID treatment group; chemistry tests, including bilirubin, AST, ALT, alkaline 85 in the oxycodone and naltrexone BID treatment group. phosphatase, GGT, LDH, total protein, albumein, urea, creatinine, calcium, inorganic phosphorus, glucose and/or 0576 All treatment groups were scheduled for QID dos uric acid); (2) urine sample for urinalysis ((e.g., urine ing to protect the double-blind Study design as shown in dipstick) including color/appearance, specific gravity, pH, Table 42. protein, Sugar, occult blood, and/or ketones); (3) urine pregnancy test for all women of childbearing potential; (4) TABLE 42 obtain up to two acetaminophen bottle numbers and dis pense acetaminophen, take-home diary and provide an Treatment QID Daily Dosing Scheme appointment card for the next visit. The Study nurse thor oughly reviewed each Section of the diary with the patient. The diary issued at the Screening Visit was to be used to Group Upon Waking Noon Afternoon Bedtime record the following information at bedtime immediately before a dose of acetaminophen was taken; (5) overall pain A. OXY - NTX OXY - NTX OXY - NTX OXY - NTX intensity (PI) in the past 24 hours; and (6) date and number B OXY OXY OXY OXY of acetaminophen doses. C Placebo Placebo Placebo Placebo 0572 Patients who had taken lower daily opioid dose D OXY - NTX Placebo OXY - NTX Placebo equivalents of oxycodone or tramadol could begin the washout period at the Screening Visit. 0573 At the conclusion of the washout period, patients 0577. The number (percentage) of subjects with opioid were randomly assigned to one of the following four treat use within one month (30 days) of first dose of study ment groups, if the required PI Scores as Specified by the medication was in the placebo group 43 of 101 (42.6%), in study were met, as shown in Table 40. the oxycodone QID group 99 of 206 (48.1%), in the oxyc odone and naltrexone QID group 85 of 206 (41.3%) and in TABLE 40 the oxycodone and naltrexone BID group 88 of 206 (42.7%). Treatment On a weekly basis, dose was to be escalated according to the Group Study Drug titration Schedule shown in 43. A. oxycodone (OXY) and naltrexone (NTX) QID B oxycodone (OXY) QID C Placebo OID D oxycodone (OXY) and naltrexone (NTX) BID Jan. 12, 2006

TABLE 43 Total Daily Group B Group C Oxycodone Group A (OXY) (Placebo) Group D Week Dose (mg) (OXY + NTX) QID QID QID (OXY + NTX) BID 1. 1O OXY 2.5 mg + NTX 2.5 mg O OXY 5 mg + NTX 0.001 mg 0.001 mg 2 2O OXY 5 mg + NTX 0.001 mg 5 mg O OXY 10 mg + NTX 0.001 mg 3 3O OXY 7.5 mg + NTX 7.5 mg O OXY 15 mg + NTX 0.001 mg 0.001 mg 4 40 OXY 10 mg + NTX 0.001 mg 10 mg O OXY 20 mg + NTX 0.001 mg 5 60 OXY 15 mg + NTX 0.001 mg 15 mg O OXY 30 mg + NTX 0.001 mg 6 8O OXY 20 mg + NTX 0.001 mg 20 mg O OXY 40 mg + NTX 0.001 mg

TABLE 44

Oswestry Disability Index Version 2 0578 Dose and adverse events were to be evaluated at each Visit. The dose was to be increased to the next dose level if the average daily bedtime PI during the last 3 days '" ------of each preceding week was >2 and no unacceptable adverse D D M M M Y Y Y Y Directions: Could you please complete this questionnaire. It is designed events were reported. The dose was to be fixed, if the to give us information as to how your back trouble has affected your average daily bedtime PI during the last 3 days of each ability to manage in everyday life. Please answer every section. Mark preceding week was S2 with no unacceptable adverse one box only in each section that most clearly describes you today. Section 1: Pain Intensity events, and the patient was to enter the 12-week fixed-dose One period of the study. For these patients, the last week of the I have no pain at the moment. titration period was to serve as the first week of the fixed The pain is very mild at the moment. dose period. Therefore, only an additional 11 weeks of D The pain is moderate at the moment. treatment were carried out. The same procedure was to occur O The pain is fairly severe at the moment. if a patient had reached 80 mg at Week 6 of the titration The pain is very severe at the moment. period with no unacceptable adverse events. D The pain is the worst imaginable at the moment. 0579. If any unacceptable study drug related adverse events were encountered, the dose was to be reduced by one Section 2: Personal care (washing, dressing, etc.) level. No more than one dose reduction was to occur. The One I can look after myself normally without causing extra pain. patient was to remain at this reduced dose for a total of 12 I can look after myself normally but it is very painful. weeks. It is painful to look after myself and I am slow and careful. 0580 For patients experiencing unacceptable adverse O I need some help but manage most of my personal care. events or intolerable pain in between Scheduled clinic visits, I need help every day in most aspects of self care. the dose level was to be decreased or increased during the D I do not get dressed, wash with difficulty and stay in bed. treatment week with the Sponsor's approval. Section 3: Lifting 0581 Patients were to record their PI every 24 hours in One their daily diary immediately before their bedtime dose. In I can lift heavy weights without extra pain. addition, adverse events and opioid-related adverse events I can lift heavy weights but it gives extra pain. were to be recorded in the daily diary. Pain prevents me from lifting heavy weights off the floor but I can manage if they are conveniently positioned, e.g. on a table.

0582. At the weekly visits (+1 day) during the 1- to Pain prevents me from lifting heavy weights but I can manage 6-week titration period, quality of analgesia and a global light to medium weights if they are conveniently positioned. assessment of Study medication were to be collected. The D I can lift only very light weights. SF-12 as shown in Table 1 and Oswestry Disability Index D I cannot lift or carry anything at all. (ODI) as shown in Table 44 were to be completed at the end of the titration period (if the titration period was 24 weeks). US 2006/0009478 A1 Jan. 12, 2006

TABLE 44-continued TABLE 44-continued Oswestry Disability Index Version 2 Oswestry Disability Index Version 2

Section 4: Walking One One I can travel anywhere without pain. Pain does not prevent me walking any distance. I can travel anywhere but it gives extra pain. D Pain prevents me walking more than 1 mile. O Pain is bad but I manage journeys over two hours. O Pain prevents me walking more than % of a mile. D Pain restricts me to journeys of less than one hour. D Pain prevents me walking more than 100 yards. Pain restricts me to short necessary journeys under 30 minutes. I can only walk using a stick or crutches. D Pain prevents me from travelling except to receive treatment. D I am in bed most of the time and have to crawl to the toilet. 0583. During the fixed-dose period, patients were to Section 5: Sitting One return to the clinic each week (t1 day) during the first two I can sit in any chair as long as I like. weeks and then at 2-week (+2 days) intervals for the I can sit in my favourite chair as long as I like. remainder of the Study. At each clinic visit, quality of O Pain prevents me from sitting for more than 1 hour. analgesia and a global assessment of Study medication was Pain prevents me from sitting for more than % an hour. to be collected. The SF-12 and ODI were to be performed Pain prevents me from sitting for more than 10 minutes. once every 4 weeks of the fixed-dose period. Pain prevents me from sitting at all. 0584) Patients were to return for a post-treatment follow up visit approximately one week (t1 day) after the final dose

of Study medication. If a patient required additional analge Section 6: Standing sic medication during the post-treatment follow-up period, I can stand as long as I want without extra pain. he/she was to be allowed to take acetaminophen, NSAIDs, I can stand as long as I want but it gives me extra pain. or COX-2 inhibitors. No opioids (or tramadol) were to be Pain prevents me from standing for more than 1 hour. allowed during this period. Pain prevents me from standing for more than % an hour. 0585 Safety was evaluated by vital signs (blood pres Pain prevents me from standing for more than 10 minutes. Sure, heart rate, respiratory rate and temperature), physical D Pain prevents me from standing at all. examinations, EKGs, clinical laboratory tests, adverse events including opioid-related adverse events, opioid tox icity assessments and the assessment of opiate withdrawal symptoms using the Short Opiate Withdrawal Scale (SOWS, One My sleep is never disturbed by pain. see Table 6 above). O My sleep is occasionally disturbed by pain. 0586 Approximately seven hundred patients with mod D Because of pain I have less than 6 hours sleep. erate to Severe chronic low back pain were to be enrolled in D Because of pain I have less than 4 hours sleep. this study. Inclusion criteria for Subjects were as follows: Because of pain. I have less than 2 hours sleep.

0587 (1) males and females who are 218 and s 70 O Pain prevents me from sleeping at al. years of age;

0588) (2) patient had persistent moderate to severe low Section 8: Sex Life (if applicable) back pain for the previous 6 months, One

My sex life is normal and causes no extra pain. 0589 (3) patient had taken one of the following anal My sex life is normal but causes some extra pain. gesic medications daily during the past 30 days prior to D My sex life is nearly normal but is very painful. screening: NSAID, COX-2 inhibitor, acetaminophen, D My sex life is severely restricted by pain. tramadol, or opioid; My sex life is nearly absent because of pain. 0590 (4) patient had received either: (a) no opioids or Pain prevents any sex life at all. a daily opioid dose equivalent of oxycodone S20 mg or tramadols 200 mg within one week prior to enrollment Section 9: Social Life into the study; or (b) a daily opioid dose equivalent of One oxycodone (>20 mg and s 160 mg) or tramadol >200 My social life is normal and causes me no extra pain. mg within one week prior to enrollment into the Study O My social life is normal but increases the degree of pain. and had undergone an opioid taper period (See above); O Pain has no significant effect on my social life apart from limit ing my more energetic interests, e.g. sport etc. 0591 (5) patient had a pain intensity score of 25 on an D Pain has restricted my social life and I do not go out as often. 11-point numerical Scale at the Screening Visit; Pain has restricted my social life to my home. 0592 (6) patient had a mean daily diary overall pain O I have no social life because of pain. intensity (taken immediately before the bedtime dose of acetaminophen) of 25 on an 11-point numerical Scale during the last 3 days of the washout period and a US 2006/0009478 A1 Jan. 12, 2006 82

confirmatory pain intensity level of 25 on an 11-point 0608 (11) patient had a history of cardiac disease numerical Scale measured at the clinic at the Baseline (Such as coronary artery disease, cardiomyopathy, con Visit; gestive heart disease, valvular disease, arrythmia, etc.), angina, cerebral aneurysm, cerebral vascular accident 0593 (7) patient was able to ambulate at least 100 (CVA), transient ischemic event (TIA) or inadequately meters, controlled hypertension; 0594 (8) females who were postmenopausal, physi cally incapable of childbearing, or practicing an accept 0609 (12) patient had a known allergy or significant able method of birth control. Acceptable methods of reaction to any of the Study medications: Oxycodone, birth control include hormonal contraceptives or maltrexone, or acetaminophen; double-barrier methods (condom or diaphragm with a 0610 (13) patient had severe impairment of pulmo Spermicidal agent or IUD). If practicing an acceptable nary function, hypercarbia, hypoxia, Significant chronic method of birth control, a negative urine pregnancy test obstructive airways disease or cor pulmonale, acute or result had been obtained at the Screening Visit; Severe bronchial asthma, Sleep apnea Syndrome or 0595 (9) patient agreed to refrain from taking any pain respiratory depression; medications other than Study drug during the washout 0611 (14) ppatient had or was Suspectedp of havin9. period and the entire treatment period. Aspirin (up to paralytic ileus, acute abdomen (serious abdominal pain 325 mg/day) was permitted for cardiovascular prophy requiring emergency Surgery), or delayed gastric emp laxis if at a stable dose one month prior to the Screening tying; Visit.; and 0612 (15) patient had a history of gastric, biliary, or 0596 (10) patient was able to understand and cooper Small intestine Surgery, or any other diseases that cause ate with Study procedures, and has signed an informed clinical malabsorption; consent form prior to entering the Study. 0613 (16) patient has chronic biliary tract disease, 0597 Exclusion Criteria for subjects were as follows: chronic pancreatitis, or inflammatory bowel disorders, 0598 (1) patient had a positive urine drug screen at the 0614) (17) patient had untreated myxedema, untreated Baseline Visit (Start of Titration Period, Week 1, Day 1) hypothyroidism, elevated intracranial preSSure, Severe NOT caused by any therapeutic medication permitted anemia, adrenocortical insufficiency, hypotension or during the Study, hypovolemia; 0599 (2) patient had low back pain secondary to 0615 (18) patient had started or stopped monoamine malignancy, inflammatory disease (rheumatic arthritis, Oxidase inhibitors, tricyclic antidepressant drugs, Sero ankylosing spondylitis, Reiter's Syndrome), fibromyal tonin reuptake inhibitors, glucosamine/chondroitin, or gia, Vertebral fracture, or infection; St. John's Wort within four weeks prior to receiving 0600 (3) patient had major Surgery within three Study medication, however, a constant dose for longer months prior to the Screening Visit or had Surgery than four weeks was acceptable; planned during the proposed Study period; 0616 (19) patient had started or stopped physical 0601 (4) patient had received oral or parenteral corti therapy, transcutaneous electrical nerve Stimulation, costeroid therapy within one month prior to the Screen chiropractic, Osteopathic, acupuncture, or other ing Visit; complementary treatment within the past four weeks or was expected to undergo any changes in these therapies 0602 (5) patient had received intraspinal infusion of in the duration of the study; any medication or implanted Spinal cord Stimulator within one month prior to the Screening Visit or had 0617 (20) patient was receiving high doses of seda plans for Such treatment during proposed Study period; tives, hypnotics or tranquilizers, 0603 (6) patient had undergone any percutaneous (i.e. 0618 (21) patient was receiving phenothiazines or discogram, epidural injection, discectomy, IDET, etc.) other agents that compromise vasomotor tone; or open (laminectomy, discectomy, fusion, instrumen tation, etc.) procedures involving the lumbosacral spine 0619 (22) patient had a history of alcohol or drug within four months prior to the Screening Visit or had abuse within the past 5 years, any Such procedures planned during the proposed Study 0620 (23) patient had a psychiatric illness or medical period; illness/condition that, in the opinion of the investigator, 0604 (7) patient was involved in an unsettled claim would interfere with the completion of study, confound Such as automobile accident, civil lawsuit, or workers the results of the Study, or pose risk to the patients, compensation pertaining to a low back injury, however, 0621 (24) patient had a history of the following neo patients with Settled claims were able to participate, plastic disease: leukemia, lymphoma, or myeloprolif erative disease, metastatic cancer, however, in patients 0605 (8) patient weighed more than 300 lbs or less with treated localized malignancies, the decision to than 100 lbs; exclude was made by the Sponsor on individual cases, 0606 (9) patient was pregnant or breast-feeding; 0622 (25) patient had AST, ALT, GGT, or alkaline 0607 (10) patient had a history of severe hepatic or phosphatase >2 times the upper limit of normal; hema renal impairment; tocrit <30%; or creatinine > 1.8 at the Screening Visit; US 2006/0009478 A1 Jan. 12, 2006 83

0623 (26) patient had previously received the oxyc BioChek iCup TM Drug Screen), if this was positive for any odone and naltrexone Study drug, drugs not caused by any therapeutic medication permitted 0624 (27) ppatient had pparticipated p in another investi during the Study, no further assessments were done and the gational drug trial or therapeutic trial within 30 days of patient did not continue in the Study); (2) review of take the Screening Visit; or home diary; (3) collect bottle(s) of acetaminophen and perform accountability; (4) baseline clinic PI rating; and (5) 0625 (28) patient had taken analgesic medication review inclusion and exclusion criteria and verify that: (a) (other than acetaminophen-a maximum of 3000 the mean daily overall pain intensity Score collected in the mg/day) during the minimum 4-day washout period diary during the last 3 days of the washout period was 25 prior to randomization. (on a scale of 0 to 10) while off all analgesic medications 0626. The physical descriptions of the drugs used for the (except acetaminophen as directed); and (b) the clinic PI at Study were as follows. Up to 2 containers of acetaminophen this visit measured 25 (on a scale of 0 to 10); and (c) from were dispensed at the Screening Visit for the minimum the Screening Visit, clinical laboratory tests results were 4-day washout period (maximum 10 days). A commercially without significant clinical abnormalities, the urine preg available Source of acetaminophen (500 mg) was Supplied. nancy test was negative (if required). The investigational drug Supplies were available in tablet dosage forms containing oxycodone HCl and naltrexone 0631 Patients meeting the study entry criteria were ran HCl, oxycodone HCl, or placebo. All of the tablet dosage domly assigned to one of the four treatment groups, as forms were indistinguishable from one another to facilitate described in Table 40 above, and were assigned a random blinding. ization number and study medication kit number. The fol 0627 The study procedures were as follows. Prior to any lowing assessments were then conducted: (1) interim medi Study-related activities, the patient provided written cal history (to identify any changes from the Screening informed consent. The Investigator explained the Study Visit); (2) vital signs; (3) SF-12 Health Survey; (4) Oswestry (characteristics of the drug Substances, required procedures, Disability Index (ODI); and (5) review and record concomi potential hazards, and possible adverse reactions) to all tant medications. Once these assessments and procedures prospective participants. were completed, study medication (one blister card) was dispensed for Week 1 of the titration period. A take-home 0628. At the first visit (Screening Visit), pre-enrollment daily diary was dispensed and an appointment card for the screening was performed. Patients who had taken a daily next visit was provided. The study nurse reviewed each opioid dose equivalent of oxycodone (>20 mg and is 160 section of the diary with the patient. The daily diaries issued mg) or tramadol >200 mg during the previous week were to at each visit were used to record the following information: have an opioid taper as described above. Patients were (1) overall PI in the past 24 hours at bedtime immediately tapered off of their opioid or tramadol medication for a prior to dosing; and (2) adverse events (including an assess Sufficient amount of time to prevent withdrawal according to ment of opioid-related adverse events). the investigator's clinical judgment and assessments were performed as described above. Patients who had taken lower 0632. During the titration period (Weeks 2-6, Day 1), daily opioid dose equivalents of oxycodone or tramadol did patients returned to the study center at weekly intervals (t1 not require a taper and could enroll in the Study at the day) for up to six weeks for the following assessments: (1) Screening Visit. opioid toxicity assessment; (2) review take-home diary (including overall daily bedtime PI and opioid-related 0629. The following assessments were conducted at the adverse events); (3) record new/changed adverse events and Screening Visit: (1) written informed consent; (2) clinic pain concomitant medications; (4) collect study medication from intensity (PI); (3) review inclusion and exclusion criteria; (4) previous week and account for used/unused Supplies; (5) detailed medical history including concomitant medications Vital signs; (6) quality of analgesia; (7) global assessment of taken one month prior to the Screening Visit; (5) complete Study medication; (8) dispense take-home daily diary; and physical examination including height, weight and Vital (8) dispense study medication (one blister card). Dose and signs; (6) EKG (QTc interval only); (7) blood samples for adverse events were evaluated at each visit. The dose was to clinical laboratory tests (hematology and chemistry tests as be increased to the next dose level if the average daily described above); (8) urine sample for urinalysis; (9) urine bedtime PI during the last 3 days of each preceding week pregnancy test for all women of childbearing potential; and was >2 and no unacceptable adverse events were reported. (10) obtain up to two acetaminophen bottle numbers and The dose was to be fixed, if the average daily bedtime PI dispense acetaminophen and take-home diary. The Study during the last 3 days of each preceding week was S2 with nurse thoroughly reviewed each Section of the diary with the no unacceptable adverse events, and the patient entered the patient. The diary issued at the Screening Visit was to be fixed-dose period of the Study. For these patients, the last used by the patient to record the following information at week of the titration period served as the first week of the bedtime immediately before a dose of acetaminophen is fixed dose period. Therefore, only an additional 11 weeks of taken: (1) overall PI in the past 24 hours and (2) date and treatment were required. The same procedure occurred if a number of acetaminophen doses. patient had reached 80 mg at Week 6 of the titration period 0630. The second visit was to establish a baseline and the with no unacceptable adverse events. If any unacceptable start of the titration period (Week 1, day 1). The patient Study drug related adverse events were encountered, the returned to the study center a minimum of four days (maxi dose was to be reduced by one level. No more than one dose mum often days) after the Screening Visit for completion of reduction can occur. The patient was to remain at this the pre-dose assessments. These included: (1) urine sample reduced dose for a total of 12 weeks. For patients experi for drug Screening using a rapid drug Screen kit (e.g., encing unacceptable adverse events or intolerable pain in US 2006/0009478 A1 Jan. 12, 2006 84 between Scheduled clinic visits, the dose level was to be morning) by the patients. In addition, there was to be a check decreased or increased during the treatment week with the for adverse events and concomitant medications. If neces Sponsor's approval. Sary, a clinic visit could be required for those patients with 0633) At the end of the titration period (if the titration clinically significant withdrawal Symptoms. period was 24 weeks), the following assessments were 0638 Patients returned to the study center approximately performed in addition to the above-described weekly assess one week (t1 day) after the last dose of study medication for ments: (1) blood Samples for clinical laboratory tests (hema a post-treatment follow-up visit. At this visit, the following tology and chemistry tests as described above); (2) urine assessments were completed: (1) review take-home diary; sample for urinalysis as described above; (3) SF-12 Health and (2) record new/changed adverse events and concomitant Survey; and (4) ODI. Patients were to remain at the last medications. titrated dose for a total of 12 weeks. No dose adjustments 0639 Patients could choose to discontinue study drug or were allowed during this period of the Study. Study participation at any time, for any reason, and without 0634) Patients returned to the study center at Weeks 1 (if prejudice. If a patient chose to discontinue Study drug early, applicable) and 2 (+1 day) of the fixed-dose period for the the investigator would request that the patient return to the following assessments: (1) opioid toxicity assessment; (2) clinic within 24 hours of Stopping the Study medication and review take-home diary (including overall daily bedtime PI complete the end-of-treatment assessments described above. and opioid-related adverse events); (3) record new/changed For patients who had been on study medication for 24 adverse events and concomitant medications; (4) collect weeks, Day 1 of the opioid withdrawal monitoring period Study medication from previous visit and account for used/ was to begin 24 hours after the last dose of Study medication. unused Supplies; (5) Vital signs; (6) quality of analgesia; (7) The investigator also requested that the patient remain in the global assessment of study medication; (8) dispense take study for the post-treatment follow-up visit. Study drug home daily diary; (9) dispense study medication (two blister assigned to patients who discontinued the Study early was cards were dispensed on Week 2, Day 8 of the fixed-dose not reassigned to another patient. period and patients instructed to Switch to the Second blister 0640 Efficacy assessments included: (1) pain intensity card after taking 7 days of study drug from the first card). (PI), (2) quality of analgesia and/or (3) global assessment of 0635 Patients returned to the study center at Weeks 4, 6, Study medication. 8, and 10 (+2 days) of the fixed-dose period for the following assessments: (1) opioid toxicity assessment; (2) review 0641) For the pain intensity (PI) scale assessment, the take-home diary (including overall daily bedtime PI and patient was prompted with the question “How would you opioid-related adverse events); (3) record new/changed rate your overall pain intensity at this time'?” and the PI score adverse events and concomitant medications; (4) collect was recorded in the clinic at the Screening and Baseline Study medication from previous visit and account for used/ Visits. Pain intensity was also assessed by prompting the unused Supplies; (5) Vital signs; (6) quality of analgesia; (7) patient with the questions “How would you rate your overall global assessment of study medication; (8) SF-12 Health pain intensity during the past 24 hours?” and a daily PI diary Survey (only at Weeks 4 & 8 of the fixed-dose period); (9) score was recorded at bedtime. For both Pain Intensity ODI (only at Weeks 4 & 8 of the fixed-dose period); (10) prompts, the response was Scored on an 11-point numerical dispense take-home daily diary; and dispense Study medi Scale (0=no pain and 10=Severe pain). cation (two blister cards dispensed and patients instructed to 0642 Quality of analgesia was assessed at clinic visits Switch to the second blister card after taking 7 days of study during the titration and fixed-dose periods. The patient was drug from the first card). prompted with the question, “How would you rate the 0636 Patients returned to the study center at the end of quality of your pain relief at this time'?” and responses were Week 12 (+2 days) of the fixed-dose period (end-of-treat Selected from poor, fair, good, very good, and excellent. ment) for the following assessments: (1) review take-home 0643 Global assessment of study medication was also diary (including overall daily bedtime PI and opioid-related assessed at clinic visits during the titration and fixed-dose adverse events); (2) record new/changed adverse events and periods. The patient was prompted with the question, “How concomitant medications; (3) collect study medication and would you rate the Study medication you received during the account for used/unused Supplies; (4) complete physical past week/past two weeks? (Please consider the quality of examination and vital signs; (5) EKG (QTc interval only); your pain relief, your Side effects, your activity level, your (6) blood Samples for clinical laboratory tests (hematology mood and Sense of well-being, etc. in this evaluation.)” and chemistry tests as described above); (7) urine Sample for Responses were Selected from poor, fair, good, Very good, urinalysis as described above; (8) quality of analgesia; (9) and excellent. global assessment of study medication; (10) SF-12 Health Survey; (11) ODI; (12) SOWS; and (13) dispense take-home 0644. Additionally, functional assessments (at baseline, daily diary (SOWS and adverse event log) for follow-up at the end of the titration period (if the titration period is 24 period and instruct patients to contact the Study center weeks), at Weeks 4 and 8 of the fixed-dose period, and at immediately if they experience Severe signs and Symptoms Week 12 of the fixed-dose period (i.e., End-of-Treatment)) of opioid withdrawal. were conducted with SF-12 (Table 1) and ODI (Table 44). 0637 The study center contacted patients (telephone vis 0.645 Clinical examinations consisted of the standard-of its) before noon once daily (for four days after the last dose care evaluations that are routinely performed as part of of Study medication) to monitor for Symptoms of opioid ongoing care for patients with moderate to Severe low back withdrawal. On each telephone call, the Study center was to pain. Safety assessments included: (1) Vital signs (blood verify that the SOWS have been completed each day (in the pressure, heart rate, respiratory rate, and temperature); (2) US 2006/0009478 A1 Jan. 12, 2006 physical examinations; (3) EKGs; (4) clinical laboratory bedtime pain intensity Scores recorded during the 3 days tests; (5) adverse events; (6) assessment of opiate with immediately prior to baseline/start of titration period Visit. drawal symptoms using the SOWS; and (7) opioid toxicity The post-baseline average daily pain intensity Scores were assessments. Opioid toxicity assessments were performed calculated as the average of the daily bedtime pain intensity during the titration period to evaluate dose escalation and the Scores recorded during the last 3 days of dosing prior to each fixed-dose period to evaluate continuation of the Study Visit. Missing data was imputed using the last-observation medication at the current dose level. The assessments carried-forward (LOCF) approach for efficacy variables in included a review of the following: (A) CNS review by the fixed-dose period. If the first visit in the fixed-dose assessing for (1) confusion, altered mental state, (2) exces period was missing, the last value in the titration period was Sive drowsiness, lethargy, stupor, and (3) Slurred speech imputed forward. Unless indicated, all testing of Statistical (new onset); (B) respiratory review by assessing for (1) Significance was two-sided, and a difference resulting in a hypoVentilation, shortness of breath, apnea and (2) p-value of equal to or less than 0.05 was considered Statis decreased respiratory rate (<8) or cyanosis, and (C) cardiac tically significant. review by assessing for heart rate <60, hypotension. If 0651 A primary efficacy endpoint was the percent patients were terminated from the Study, the end-of-treat change from baseline to the end of the fixed-dose period ment assessments and opioid withdrawal monitoring (as (Week 12) in average daily pain intensity. The percent needed) were completed. change from baseline was calculated as PI(baseline)-PI 0646 The randomization schedule was computer gener (fixed-dose)/PI(baseline)* 100. Data was summarized ated using a permuted block algorithm and randomly allo descriptively by treatment group. An analysis of covariance cated Study medication to randomization numbers. The (ANCOVA) model including treatment and center as effects randomization numbers were assigned Sequentially through and baseline pain intensity as the covariate was used for a central System as patients were entered into the Study. The global and pairwise inferences. Separate models were used randomization Schedule was Stratified by patient SeX. Inves to evaluate both the treatment by center and treatment by tigative site was not a blocking factor in the randomization baseline pain intensity interaction terms. Schedule. When three treatment groups were under Study, patients were assigned to the groups in a ratio of 2:2:1. When 0652) A primary comparison of interest was oxycodone four treatment groups were under Study, after ~50 patients and naltrexone (e.g., BID or QID) versus oxycodone (e.g., had been enrolled in the three groups studied initially (-20 QID). Secondary analyses included actual and percent patients each in the oxycodone and naltrexone QID and change from baseline values of daily pain indeX, SF-12, and oxycodone QID arms and ~10 patients in the placebo arm), Oswestry disability index summarized descriptively by patients were assigned to the groups in a ratio of 2:2:1:3 for treatment group for both the titration and fixed-dose periods. Some blocks and a ratio of 2:2:1:2 for other blocks. The Treatments were compared globally and in pairwise fashion larger Size blocks were spread evenly throughout the Smaller at each visit in the fixed-dose period using an ANCOVA Size blockS. Varying the treatment assignment ratio and model that included treatment and center as effects and block sizes throughout the randomization Schedule accom baseline pain intensity as the covariate. Separate models modated for 20 oxycodone and naltrexone BID patients not were used to evaluate both the treatment by center and enrolled initially and ensured that approximately equal num treatment by baseline pain intensity interaction terms. bers of patients were enrolled in the oxycodone and naltr 0653 Global assessment and quality of analgesia ratings exone BID, oxycodone and naltrexone QID and oxycodone were Summarized descriptively by treatment group for both QID groups at the conclusion of the enrollment period. the titration and fixed-dose periods. Treatments were com 0647. The primary analysis population was the intent-to pared at each visit in the fixed-dose period, globally and in treat (ITT) population. The ITT population consisted of all pairwise fashion, using the Cochran-Mantel-HaenSZel row patients who take Study medication and was used for both mean Scores (CMH-RMS) test, using equally spaced scores. efficacy and Safety analyses. In the event that a patient was 0654 Adverse events reported on case report forms were randomized incorrectly or was administered the incorrect mapped to preferred terms and body Systems using the Study medication, the patient was analyzed according to the MedDRA coding dictionary. The number and percent of Study drug actually received. patients reporting each event were Summarized by treatment 0648 Demographic variables and baseline patient char group and dosing period. Incidence of adverse events by acteristics were Summarized descriptively by treatment maximum reported Severity was also tabulated. group and overall. Demographic variables included age, 0655 Treatment groups were examined for differences in weight, height, gender, and ethnicity while baseline patient the incidence (e.g., frequency), Severity and/or duration characteristics included baseline pain intensity, baseline (e.g., daily or over a period of drug treatment) of Selected SF-12, and baseline Oswestry Disability Index. Study drug opioid-associated adverse events including constipation, administration, prior medications and concomitant medica diZZiness, Somnolence, pruritis, nausea and vomiting. tions were also Summarized. 0656 Change from baseline (either the Screening Visit or 0649. The following endpoints were summarized and the Start of Titration Period Visit, whichever occurs later and analyzed within both dosing periods (titration and fixed has data present) were Summarized descriptively for vital dose): (1) daily pain intensity ratings; (2) quality of anal Signs and QTc interval. Laboratory data were Summarized gesia; (3) global assessment of study medication; (4) SF-12; descriptively on the original Scale, change from baseline and (5) Oswestry Disability Index. (Screening Visit), and in terms of the normal range. 0650. The baseline average daily pain intensity score for 0657 Each assessment of opiate withdrawal symptoms each patient was calculated as the average of the daily using SOWS on Days 1 through 4 of opioid withdrawal US 2006/0009478 A1 Jan. 12, 2006 86 monitoring were reduced to an average System Score and doses (e.g., for the entire Study period including titration and were Summarized in terms of changes from baseline, which fixed-dose period) for the treatment groups. was defined as the in-clinic assessment at the end of treat ment visit (Week 12 of the fixed-dose period). 0661. One efficacy assessment was a pain assessment. Pain intensity Scores or ratings were measured for this Study 0658) A primary efficacy endpoint was the percent as described above and reported as actual values, as well as change from baseline to the end of the fixed-dose period changes from baseline, and percent changes from baseline to (Week 12) in average daily pain intensity. A primary com fixed dose, for baseline as shown in Table 45A and each parison of interest was oxycodone and naltrexone (e.g., BID week of Weeks 1-12 of the fixed-dose period as shown in or QID) versus oxycodone (e.g., QID). Tables 45B through -45KK. For example, Tables 45B and 0659. It was expected that there would be at least a 40% 45JJ show the actual values for pain intensity at Week 1 and drop out rate in the study before the 12 week fixed-dose Week 12, respectively, of the fixed-dose period; Tables 45C period concluded. With this high drop out rate, along with and 45JJ show the changes in pain intensity from baseline to clinical considerations, it was estimated that enrolling 200 Week 1 and Week 12, respectively, of the fixed-dose period; patients each in the oxycodone and naltrexone BID, oxyc and Tables 45D and 45KKshow the percent changes in pain odone and naltrexone QID and oxycodone treatment groups, intensity from baseline to Week 1 and Week 12, respectively, and 100 patients in the placebo group would be sufficient to of the fixed-dose period. An efficacy endpoint for this Study detect clinically meaningful differences between treatments was percent change from baseline to the end of the fixed and to provide adequate Safety and exposure data. dose period (Week 12) in average daily pain intensity as 0660 From this clinical study, various assessments were shown in Table 45KK. Reductions in mean PI occurred at made, including a pain assessment (e.g., pain intensity), a each week of the fixed-dose period in all active treatment quality of analgesia assessment, a global assessment, a groups as compared to placebo, and the difference in pain functional assessment (e.g., using the OSwestry Disability intensity of each active treatment group versus placebo was Index (ODI) and/or SF-12 Health Survey), an assessment of statistically significant at each of Weeks 1-12 of the fixed withdrawal symptoms (e.g., using the Short Opioid With dose period. There were no Statistically significant differ drawal Scales (SOWS)), as well as assessments of average ences between active treatment groups (e.g., when one titration doses (e.g., for the titration period), average fixed active treatment group was compared to another active doses (e.g., for the fixed-dose period), and average study treatment group).

TABLE 45A

PAIN INTENSITY - BY WEEK LAST OBSERVATION CARRIED FORWARD IMPUTATION ANALYSIS POPULATION: INTENT TO TREAT POPULATION

PLACEBOOID OXY OID OXY + NTX OID OXY - NTXBID TOTAL (N = 101) (N = 206) (N = 206) (N = 206) (N = 719) BASELINE MEAN (SD) 7.7 (1.44) 7.6 (1.36) 7.3 (1.36) 7.6 (1.33) 7.5 (1.37) MEDIAN 7.7 7.7 7.3 7.7 7.3 MINIMUM (MAXIMUM) 5.0 (10.0) 5.0 (10.0) 4.7 (10.0) 4.7 (10.0) 4.7 (10.0) N 101 2O6 2O6 2O6 719 MODELP-VALUES TREATMENT1 SEX I1 TREATMENT SEX 2 O.805 PAIRWISE COMPARISON P-VALUES 1 PLACEBOOID 0.444 O.OO8 O.510 OXY OID O.O21 O.894 OXY + NTX OID

NOTE: USING AVERAGE PAIN INTENSITY OF LAST THREE DAYS WITHIN EACH DOSING WEEK. 1 P-VALUES FROM ANCOVA MODEL INCLUDING TREATMENT AS THE MAIN EFFECT AND SEX AS A BLOCKING FACTOR. 2 P-VALUES FROM ANCOVA MODEL DEFINED IN 1 INCLUDING TREATMENT SEX INTERACTION TERMS.

0.662

TABLE 45B

PAIN INTENSITY - BY WEEK LAST OBSERVATION CARRIED FORWARD IMPUTATION