EP1680143A2 - Traitement d'etats arthritiques, d'inflammation chronique ou de la douleur - Google Patents

Traitement d'etats arthritiques, d'inflammation chronique ou de la douleur

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Publication number
EP1680143A2
EP1680143A2 EP04795362A EP04795362A EP1680143A2 EP 1680143 A2 EP1680143 A2 EP 1680143A2 EP 04795362 A EP04795362 A EP 04795362A EP 04795362 A EP04795362 A EP 04795362A EP 1680143 A2 EP1680143 A2 EP 1680143A2
Authority
EP
European Patent Office
Prior art keywords
pain
use according
subject
amount
opioid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04795362A
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German (de)
English (en)
Inventor
Grant L. Schoenhard
Nadav Friedmann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pain Therapeutics Inc
Original Assignee
Pain Therapeutics Inc
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Filing date
Publication date
Application filed by Pain Therapeutics Inc filed Critical Pain Therapeutics Inc
Publication of EP1680143A2 publication Critical patent/EP1680143A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to methods and materials, including novel compositions, dosage forms and methods of administration, useful for the treatment of arthritic conditions, inflammation associated with a chronic condition, and/or chronic pain, including pain from arthritic conditions or inflammation, using opioid antagonists, including combinations of opioid antagonists and opioid agonists.
  • the methods and materials provide human subjects with an alleviation of one or more symptoms or signs of an arthritic condition, inflammation associated with a chronic condition or chronic pain, including, for example, reduced pain, reduced stiffness and/or improved physical function.
  • Methods and materials of the invention comprising opioid antagonists or combinations of opioid antagonists and agonists may optionally include one or more additional therapeutic agents.
  • the inflammatory process involves a series of " events that can be elicited by numerous stimuli (e.g., infectious agents, ischemia, antigen-antibody interactions, and thermal or other physical injury). At a macroscopic level, inflammation usually is accompanied by the familiar clinical signs of erythema, edema, tenderness (hyperalgesia), and pain.
  • stimuli e.g., infectious agents, ischemia, antigen-antibody interactions, and thermal or other physical injury.
  • inflammation usually is accompanied by the familiar clinical signs of erythema, edema, tenderness (hyperalgesia), and pain.
  • Inflammatory responses occur in three distinct phases, each apparently mediated by different mechanisms: (1) an acute transient phase, characterized by local vasodilation and increased capillary permeability; (2) a delayed, subacute phase, most prominently characterized by infiltration of leukocytes and phagocytic cells; and (3) a chronic proliferative phase, in which tissue degeneration and fibrosis occur.
  • Many different mechanisms are involved in inflammation (see, e.g., Gallin et al, eds. INFLAMMATION: BASIC PRINCIPLES AND CLINICAL CORRELATES (2nd ed., 1992); Kelly et al, eds. TEXTBOOK OF RHEUMATOLOGY (4th ed. 1993)).
  • osteoarthritis is a degenerative joint disease, characterized by the breakdown of the joint's cartilage. Cartilage breakdown causes bones to rub against each other, causing pain and/or loss of movement. Most commonly affecting middle-aged and older people, osteoarthritis can range from very mild to very severe. It affects hands and weight-bearing joints such as knees, hips, feet, the back and/or the neck.
  • Rheumatoid arthritis involves inflammation in the lining of the joints and/or other- internal organs. Rheumatoid arthritis typically affects many different joints. It is typically chronic, but can be a disease of flare-ups. Rheumatoid arthritis is a systemic disease that affects the entire body and is one of the most common forms of arthritis. It is characterized by the inflammation of the membrane lining the joint (the synovium), which causes pain, stiffness, warmth, redness and/or swelling. The inflamed synovium can invade and damage bone and cartilage. Inflammatory cells release enzymes that may digest bone and cartilage. The involved joint can lose its shape and alignment, resulting in pain and loss of movement.
  • synovium the membrane lining the joint
  • Prostaglandins are recognized as participating in the inflammatory process.
  • IL-1 and TNF appear to work in concert with each other and with growth factors (such as granulocyte/macrophage colony stimulating factor, GM-CSF) and other cytokines, such as IL-8 and related chemotactic cytokines (chemokines), which can promote neutrophil infiltration and activation.
  • TNF is composed of two closely related proteins: mature TNF (TNF ⁇ ) and lymphotoxin (TNF ⁇ ).
  • cytokines and growth factors contribute to manifestations of the inflammatory response.
  • concentrations of many of these factors are increased in the synovia of patients with arthritides, such as rheumatoid arthritis.
  • concentration of peptides, such as substance P, which promotes firing of pain fibers also is increased at such sites.
  • cytokines and growth factors have been implicated as having anti-inflammatory activity.
  • TGF- ⁇ i fransforming growth factor- ⁇ i
  • IL-10 interleukin 10
  • IFN- ⁇ interferon gamma
  • Histamine is also a mediator of the inflammatory process. Although several Hi histamine-receptor antagonists are available, they are useful only for the treatment of vascular events in the early transient phase of inflammation. Bradykinin and 5-hydroxytryptamine (serotonin, 5-HT) also may play a role in mediating inflammation, but their antagonists ameliorate only certain types of inflammatory responses. Specific inhibitors of leukotriene synthesis, (zileuton, a 5-lipoxygenase inhibitor) and cysteinyl leukotriene-receptor antagonists (montelukast and zafirlukast) exert anti-inflammatory actions and have been approved for the treatment of asthma. Another lipid autacoid, platelet-activating factor (PAF), has been implicated as an important mediator of inflammation, and inhibitors of its synthesis and action are under study.
  • PAF platelet-activating factor
  • rheumatoid arthritis Although the pathogenesis of rheumatoid arthritis is largely unknown, it appears to be an autoimmune disease driven primarily by activated T cells, giving rise to T cell-derived cytokines, such as IL-1 and TNF. Although activation of B cells and the humoral response also are evident, most of the antibodies generated are IgG of unknown specificity, apparently elicited by polyclonal activation of B cells rather than from a response to a specific antigen. [11] Many cytokines, including IL-1 and TNF, have been found in the rheumatoid synovium.
  • cytokines such as IL-1 or TNF.
  • cytokines such as IL-1 or TNF.
  • some of the actions of these cytokines are accompanied by the release of prostaglandins and/or thromboxane A , only their pyrogenic effects are blocked by inhibitors of cyclooxygenase.
  • many of the actions of the prostaglandins are inhibitory to the immune response, including suppression of the function of helper T cells and B cells and inhibition of the production of IL-1.
  • LL-8 appear to be particularly important in eliciting the pain associated with inflammation. These agents liberate prostaglandins and probably other mediators that promote hyperalgesia. Neuropeptides, such as substance P and calcitonin gene-related peptide, also may be involved in eliciting pain.
  • Nonsteroidal anti-inflammatory drugs are known and prescribed for their anti-inflammatory, antipyretic, and analgesic effects.
  • NSAIDs are known to inhibit the biosynthesis of prostaglandins.
  • NSAIDs generally do not inhibit the formation of eicosanoids such as the leukotrienes, which also contribute to inflammation, nor do they affect the synthesis of numerous other inflammatory mediators.
  • NSAIDs may have other actions that contribute to their therapeutic effects.
  • acetaminophen While most NSAIDs are antipyretic, analgesic, and anti-inflammatory, an important exception is acetaminophen, which is antipyretic and analgesic but is largely devoid of anti- inflammatory activity. This can be explained by the fact that acetaminophen effectively inhibits cyclooxygenases in the brain but not at sites of inflammation in peripheral tissues.
  • Aspirin is a known NSAID that covalently modifies both cyclooxygenase- 1 (COX-1) and cyclooxygenase-2 (COX-2) primarily via inhibition, thus resulting in an irreversible inhibition of cyclooxygenase activity.
  • COX-1 cyclooxygenase- 1
  • COX-2 cyclooxygenase-2
  • CELEBREX ® celecoxib
  • CELEBREX ® is a nonsteroidal anti-inflammatory drug that exhibits anti- inflammatory, analgesic, and antipyretic activities.
  • CELEBREX ® is chemically designated as 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-lH- pyrazol-1-yl] benzene-sulfonamide and is a diaryl substituted pyrazole.
  • BEXTRA ® valdecoxib
  • valdecoxib is a nonsteroidal anti-inflammatory drug that exhibits anti- inflammatory, analgesic, and antipyretic activities.
  • CELEBREX ® and BEXTRA ® are used to treat osteoarthritis and are said to demonstrate significant reduction in joint pain compared to placebo.
  • CELEBREX ® and BEXTRA are also used to treat rheumatoid arthritis and are said to demonstrate significant reduction in joint tenderness/pain and joint swelling compared to placebo.
  • CELEBREX ® and BEXTRA ® share many of the side effects of other NSAIDs and can cause discomfort and (relatively rarely) more serious side effects, such as gastrointestinal bleeding.
  • NSAIDs such as aspirin, acetaminophen, CELEBREX ® , and BEXTRA ® , find clinical application as anti-inflammatory agents in the treatment of musculoskeletal disorders, such as rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis.
  • Chronic treatment of patients with rofecoxib and celecoxib has been shown to be effective in suppressing inflammation without the gastric toxicity that is associated with treatment with nonselective NSAIDS.
  • NSAIDs provide only symptomatic relief from the pain and inflammation associated with the disease and do not arrest the progression of pathological injury to tissue.
  • NSAIDs In addition to sharing many therapeutic activities, NSAIDs share several unwanted side effects. The most common is a risk of gastric or intestinal ulceration that sometimes can be accompanied by anemia from the resultant blood loss, though the selective COX-2 inhibitors pose less risk of gastric ulceration.
  • Other side effects of NSAIDs that result from blockade of the synthesis of endogenous prostaglandins and thromboxane A 2 include disturbances in platelet function, the prolongation of gestation or spontaneous labor, premature closure of the patent ductus, and changes in renal function. Other risks include anaphylactoid reactions, angiodema, anemia, fluid retention, borderline elevations of one or more liver tests, and notable elevations of ALT or AST.
  • Morphine sulfate has been used in clinical studies to treat patients with chronic back pain.
  • a once-daily pain product of morphine sulfate extended-release capsules identified as ANINZA ® is stated by Ligand Pharmaceuticals Incorporated (San Diego, California, USA) to provide stable analgesia for one year in patients with chronic back pain, without increases in dose or the use of rescue medicines.
  • Patients with chronic, moderate-to-severe back pain who took ANINZA ® once-daily were reported to experience, on average, stable pain control for the duration of the study, as measured both by the lack of change in pain intensity, and by the stable average dose.
  • ANINZA ® was reported to maintain pain control while patients use approximately one less dose of rescue medicine per day compared to baseline. It was further reported that, with the exception of the improvement observed in the first month, there were no statistically significant or clinically meaningful changes in pain intensity during the one-year study, indicating that ANINZA ® provided stable, long-term analgesia. Side effects were similar to those typically observed with opioid therapy, and included nausea, constipation and flu-like syndrome.
  • compositions for treating a subject with IBS which comprise an effective dose of an opioid receptor antagonist, and a pharmaceutically acceptable carrier.
  • U.S. Patent Application Publication No. 2002013776 Al (the disclosure of which is incorporated herein by reference) describes a method for increasing analgesic potency of a bimodally-acting opioid agonist in a subject, by inl ibiting GMl-ganglioside in nociceptive neurons.
  • the publication describes methods for treating pain, including methods for treating chronic pain, in a subject in need of treatment thereof. Additionally, a method is described for treating tolerance to or an addiction to a bimodally-acting opioid agonist in a subject in need of treatment thereof.
  • a pharmaceutical composition of analgesic agents and a pharmaceutically- acceptable carrier is described.
  • U.S. Patent Application Publication No. 20030191147 Al (the disclosure of which is incorporated herein by reference) describes novel dosage forms, pharmaceutical compositions, kits, and methods of administration of an opioid antagonist, including in an amount of at least about 0.0001 mg to about or less than about 1.0 mg, including from about 0.0001 mg to less than about 0.5 mg.
  • solid oral dosage forms comprising an opioid antagonist and another active ingredient, such as an opioid agonist.
  • immediate release oral dosage forms and concurrent release dosage forms comprising an opioid antagonist and another active ingredient.
  • the present invention provides methods and materials, including novel compositions, dosage forms and methods of administration, useful for the treatment of arthritic conditions, inflammation associated with a chronic condition or chronic pain, including pain from arthritic conditions or inflammation using opioid antagonists, including combinations of opioid antagonists and opioid agonists.
  • Methods and materials of the invention provide treatment for pain, wherein the pain is moderate to severe.
  • Methods and materials of the present invention provide human subjects with alleviation of one or more symptoms or signs of the arthritic condition, inflammation associated with a chronic condition or chronic pain, including, for example, alleviation of pain, alleviation of stiffness and/or improvement of physical function.
  • Methods and materials of the invention comprising opioid antagonists or combinations of opioid antagonists and agonists may optionally include one or more additional therapeutic agents.
  • the present invention is directed to methods and materials for treating an arthritic condition in a human subject by administering to the subject an opioid antagonist, wherein the amount of the antagonist is effective for enhancing the potency of an opioid agonist for alleviating one or more symptoms or signs associated with the arthritic condition.
  • the present invention is directed to methods and materials for treating an arthritic condition in a human subject by administering to the subject an opioid agonist and an opioid antagonist, wherein the amount of the agonist and the amount of the antagonist together are effective for alleviating one or more symptoms or signs associated with the arthritic condition.
  • the present invention is directed to methods and materials for inhibiting progression of an arthritic condition in a human subject by administering to the subject an opioid antagonist, wherein the amount of the antagonist is effective for enhancing the potency of an opioid agonist for inhibiting progression of the arthritic condition.
  • the present invention is directed to methods and materials for inhibiting progression of an arthritic condition in a human subject by administering to the subject an opioid agonist and an opioid antagonist wherein the amount of the agonist and the amount of the antagonist together are effective for inhibiting progression of the arthritic condition.
  • the present invention is directed to methods and materials for reversing damage associated with an arthritic condition in a human subject by administering to the subject an opioid antagonist, wherein the amount of the antagonist is effective for enhancing the potency of an opioid agonist for reversing damage associated with the arthritic condition.
  • the present invention is directed to methods and materials for reversing damage associated with an arthritic condition in a human subject by administering to the subject an opioid agonist and an opioid antagonist, wherein the amount of the agonist and the amount of the antagonist together are effective for reversing damage due to the arthritic condition.
  • the present invention is directed to methods and materials for treating inflammation associated with a chronic condition in a human subject by administering to the subject an opioid antagonist, wherein the amount of the antagonist is effective for enhancing the potency of an opioid agonist for alleviating one or more symptoms or signs associated with the chronic condition.
  • the present invention is directed to methods and materials for treating inflammation associated with inflammation in a human subject by administering to the subject an opioid agonist and an opioid antagonist, wherein the amount of the agonist and the amount of the antagonist together are effective for alleviating one or more signs or symptoms associated with the inflammation.
  • the present invention is directed to methods and materials for ihibiting tissue or cellular damage resulting from inflammation associated with a chronic condition in a human subject by administering to the subject an opioid antagonist, wherein the amount of the antagonist is effective for enhancing the potency of an opioid agonist for inhibiting the tissue or cellular damage resulting from the inflammation.
  • the present invention is directed to methods and materials of inhibiting tissue or cellular damage resulting from inflammation associated with a chronic condition in a human subject by administering to the subject an opioid agonist and an opioid antagonist, wherein the amount of the agonist and the amount of the antagonist together are effective for inhibiting the tissue or cellular damage resulting from the inflammation.
  • the present invention is directed to methods and materials for reversing tissue or cellular damage resulting from inflammation associated with a chronic condition in a human subject by administering to the subject an opioid antagonist, wherein the amount of the antagonist is effective for enhancing the potency of an opioid agonist for reversing the damage resulting from the inflammation.
  • the present invention is directed to methods and materials for reversing tissue or cellular damage resulting from inflammation associated with a chronic condition in a human subject by administering to the subject an opioid agonist and an opioid antagonist, wherein the amount of the agonist and the amount of the antagonist together are effective for reversing the damage due to the inflammation.
  • the present invention is directed to methods and materials for treating chronic pain by administering to a human subject with chronic pain an opioid antagonist, wherein the amount of the opioid antagonist is effective for enhancing the potency of an opioid agonist to attenuate the chronic pain.
  • Chronic pain may result from various abnormal or compromised states (e.g., diseased), including but not limited to osteoarthritis, rheumatoid arthritis, psoriatic arthritis, back pain, cancer, injury or trauma.
  • the present invention is directed to methods and materials for treating chronic pain by administering to a human subject with chronic pain an opioid agonist and an opioid antagonist, wherein the amount of the agonist and the amount of the antagonist together are effective to attenuate the chronic pain.
  • the present invention is directed to methods and materials for dosing an opioid antagonist administered to a human subject.
  • An amount of an opioid antagonist and an amount of an opioid agonist are administered to the subject.
  • One or more symptoms or signs of an arthritic condition, inflammation associated with a chronic condition, or chronic pain are assessed.
  • a level of the opioid antagonist or a surrogate of the opioid antagonist in a sample from the subject is measured.
  • the amount of the opioid antagonist or the amount of the opioid agonist to the subject is adjusted based on the measured level.
  • the present invention is directed to methods and materials for dosing an opioid antagonist administered to a human subject.
  • An amount of an opioid antagonist and an amount of an opioid agonist are administered to the subject.
  • One or more symptoms or signs of an arthritic condition, inflammation associated with a chronic condition, or chronic pain are assessed.
  • the amount of the opioid antagonist administered to the subject is adjusted if one or more of the assessed symptoms or signs are not alleviated to a desired extent.
  • the present invention is directed to methods and materials for dosing an opioid antagonist administered to a human subject.
  • a level of the opioid antagonist or a surrogate of the opioid antagonist in a sample from a subject is measured.
  • the amount of the opioid antagonist adn inistered to the subject is adjusted if the measured level is outside a predetermined range.
  • the present invention is directed to methods and materials for determining the amount of an opioid antagonist or opioid agonist to be administered to a human subject.
  • One or more symptoms or signs of an arthritic condition, inflammation associated with a chronic condition, or chronic pain, in a human subject being administered an opioid antagonist and an opioid agonist is assessed.
  • a level of the opioid antagonist or a surrogate of the opioid antagonist in a sample obtained from the human subject is measured.
  • the level of 6 ⁇ -naltrexol can be measured as a surrogate.
  • the 6 ⁇ -naltrexol level (e.g., the concentration of 6 ⁇ -naltrexol in a plasma sample) can be a surrogate marker for assessing one or more symptoms or signs of an arthritic condition, inflammation associated with a chronic condition, or chronic pain.
  • the amount of the opioid antagonist or the amount of the opioid agonist for administration to the human subject is adjusted.
  • the present invention is directed to methods and materials for reducing the level of a biomarker in a human subject having an arthritic condition, inflammation associated with a chronic condition, or chronic pain, wherein a composition comprising an opioid antagonist and optionally an opioid agonist is administered to the human subject.
  • the present invention is directed to methods and materials for monitoring the response of a human subject being treated for an arthritic condition, inflammation associated with a chronic condition, or chronic pain, by administering an opioid antagonist and optionally an opioid agonist.
  • the level of one or more one biomarker(s) in a first sample from the subject is determined prior to treatment with the opioid antagonist and optionally the opioid agonist.
  • the level of the biomarker in at least a second sample from the subject is determined subsequent to the initial treatment with the opioid antagonist and optionally the opioid agonist.
  • the level of the biomarker in the second sample is compared with the level of the biomarker in the first sample.
  • a change in the level of the biomarker in the second sample compared to the level of the biomarker in the first sample indicates the effectiveness of the treatment.
  • One or more symptoms and signs of arthritic conditions, inflammation associated chronic conditions or chronic pain are alleviated (e.g., ameliorated, attenuated, reduced, diminished, blocked, inhibited or prevented), by methods and materials of the invention, for example, as measured by an alleviation (e.g., amelioration, attenuation, reduction, diminishment, blockage, inhibition or prevention) of pain, stiffness, or difficulty in physical function.
  • alleviated e.g., ameliorated, attenuated, reduced, diminished, blocked, inhibited or prevented
  • the present invention is directed to novel compositions, dosage forms, kits, and other materials comprising an opioid antagonist for use in or with the foregoing methods including wherein the amount of the antagonist is effective for enhancing the potency of an opioid agonist for alleviating one or more symptoms or signs associated with an arthritic condition, inflammation associated with a chronic condition, or chronic pain, and including compositions, dosage forms, kits, and other materials with an opioid agonist and an opioid antagonist, including wherein the amount of the agonist and the amount of the antagonist together are effective for alleviating one or more symptoms or signs associated with an arthritic condition, inflammation associated with a chronic condition, or chronic pain.
  • Symptoms and signs of arthritic conditions and inflammation resulting from chronic conditions are alleviated (e.g., ameliorated, attenuated, reduced, diminished, blocked, inhibited or prevented), by methods and materials of the invention, for example, as measured by an alleviation (e.g., amelioration, attenuation, reduction, diminishment, blockage, inhibition or prevention) of pain, stiffness, and/or difficulty in physical function.
  • alleviated e.g., ameliorated, attenuated, reduced, diminished, blocked, inhibited or prevented
  • the present invention provides methods and materials comprising opioid antagonists, including opioid agonists and antagonists, that provide greater pain relief, better pain control, improved function, with no change in side effect profile, even with chronic administration including as compared with methods and materials without opioid antagonists.
  • Advantages of methods and materials of the invention include enhanced and prolonged analgesia, prevention of tolerance and continued protection against tolerance even with chronic administration, reversal of opioid agonists-induced hyperalgesia, prevention of physical dependence or withdrawal, decreased rewarding euphoric side effect, and/or decreased potential for relapse/addiction.
  • Fig. 1 shows plasma concentrations (mean ⁇ SEM) of oxycodone (ng/mL) in the three treatment groups from the clinical study conducted as described in Example 1 : oxycodone QID represented as red circles (o); the combination drug of oxycodone and naltrexone QID represented as green triangles ( ⁇ ); and the combination drug of oxycodone and naltrexone BID represented as pink squares ( ⁇ ).
  • oxycodone QID represented as red circles (o)
  • the combination drug of oxycodone and naltrexone QID represented as green triangles ( ⁇ )
  • the combination drug of oxycodone and naltrexone BID represented as pink squares ( ⁇ ).
  • Example 2 shows plasma concentrations (mean ⁇ SEM) of oxymorphone (ng/mL) in the three treatment groups from the clinical study conducted as described in Example 1 : oxycodone QID represented as the bar having diagonal lines; the combination drag of oxycodone and naltrexone QID represented as the bar having diamonds; the combination drug of oxycodone and naltrexone BID represented as the darker bar having polka dots.
  • FIG. 3 shows plasma concentrations (median ⁇ quartiles) of oxycodone (ng/mL) after the final dose in the three treatment groups from the clinical study conducted as described in Example 1.
  • Fig. 4 shows log-transformed plasma concentrations (median ⁇ quartiles) of oxycodone after the final dose in the three treatment groups from the clinical study conducted as described in Example 1.
  • FIG. 5 shows log-transformed plasma concentrations (median ⁇ quartiles) of oxymorphone after the final dose in the three treatment groups from the clinical study conducted as described in Example 1.
  • Fig. 6 shows dose-normalized plasma concentrations (mean ⁇ SEM) of oxycodone
  • oxycodone QID represented as red circles (o); the combination drug of oxycodone and naltrexone QID represented as green triangles (A); and the combination drug of oxycodone and naltrexone BID represented as pink squares (D).
  • Fig. 7 shows plasma concentrations (mean ⁇ SEM) of 6 ⁇ -naltrexol (pg/mL) for two of the treatment groups from the clinical study conducted as described in Example 1: the combination drug of oxycodone and naltrexone QID represented as the bar having diamonds; the combination drug of oxycodone and naltrexone BID represented as the darker bar having dots.
  • Fig. 8 shows efficacy measures versus oxycodone concentrations after the final dose for the three treatment from the clinical study conducted as described in Example 1 : oxycodone QID represented as black circles; the combination drug of oxycodone and naltrexone BID represented as red squares; the combination drug of oxycodone and naltrexone QID represented as green diamonds. [61] Fig.
  • Fig. 10 shows efficacy measures versus 6 ⁇ -naltrexol concentrations after the final dose for two of the treatment groups from the clinical study conducted as described in Example 1: the combination drug of oxycodone and naltrexone BID represented as black circles; the combination drug of oxycodone and naltrexone QID represented as red squares.
  • Fig. 11 shows the percent change in pain intensity reported by some of the subjects in
  • Fig. 12 shows the percent change in pain intensity reported by subjects in Table 23 who received the BID dosing regimen vs. 6 ⁇ -naltrexol plasma concentrations measured for those subjects as described in Example 3.
  • Fig. 13 shows steps in a process for the preparation of dosage forms of opioid agonist and opioid antagonist.
  • the present invention provides methods and materials, including novel compositions, dosage forms and methods of administration, useful for the treatment of arthritic conditions, inflammation associated with a chronic condition, and/or chronic pain, including pain or other symptoms or signs associated with arthritic conditions or inflammation associated with chronic conditions, using opioid antagonists, including combinations of opioid antagonists and opioid agonists.
  • the methods and materials provide human subjects with alleviation of one or more of such symptoms or signs including, for example, reduced pain, reduced stiffness and/or improved physical function.
  • Methods and materials of the invention comprising opioid antagonists, including combinations opioid antagonists and agonists may optionally include one or more additional therapeutic agents.
  • the present invention provides methods and materials for treating arthritic conditions and/or inflammation associated with chronic conditions in a human subject by administering to the subject an opioid antagonist or an opioid agonist with an opioid antagonist.
  • the amount of an opioid antagonist is effective to enhance the potency of an opioid agonist for alleviating one or more symptoms or signs associated with an arthritic condition or inflammation associated with a chronic condition, for example, symptoms or signs such as pain, stiffness or difficulty in physical function.
  • the present invention provides methods and materials for inhibiting progression of an arthritic condition or inflammation associated with chronic conditions in a human subject by administering to the subject an opioid antagonist or an opioid agonist with an opioid antagonist.
  • the amount of an opioid antagonist is an amount effective for enhancing the potency of an opioid agonist for inhibiting progression of the arthritic condition or chronic conditions associated with inflammation.
  • the present invention thus provides methods and materials for inhibiting the change or progression in a subject from a normal or uncompromised state (e.g., healthy) to an abnormal or compromised state (e.g., diseased), as indicated, for example, by a symptom or sign associated with an arthritic condition, inflammation from a chronic condition or clironic pain.
  • the progression of an arthritic condition or inflammation associated with a chronic condition can be measured by a variety of methods, including by radiography, by measuring levels of cytokines and/or by measuring B cell and T cell subtype ratios.
  • the present invention provides methods and materials for reversing damage associated with an arthritic condition or inflammation associated with chronic conditions in a human subject comprising administering to the subject an opioid antagonist or an opioid agonist with an opioid antagonist.
  • the amount of an opioid antagonist is an amount effective for enhancing the potency of an opioid agonist for reversing damage due to the arthritic condition or inflammation associated with chronic conditions.
  • the present invention thus provides methods and materials for reversing the change or progression in a subject from a normal or uncompromised state to an abnormal or compromised state as indicated, for example, by a symptom or sign associated with an arthritic condition, inflammation from a chronic condition or chronic pain.
  • the progression of the arthritic condition or inflammation associated with chronic conditions can be measured by a variety of methods, including by radiography, by measuring levels of cytokines and/or by measuring B cell and T cell subtype ratios.
  • the present invention provides methods and materials for treating chronic pain by administering to a human subject with chronic pain an opioid antagonist or the amount of an opioid agonist with an opioid antagonist.
  • Chronic pain can include pain that is headache, lower back pain, cancer pain, arthritis pain, infection pain, neurogenic pain or psychogenic pain.
  • Methods and materials are effective for the treatment of moderate to severe pain and particularly severe pain.
  • the amount of an opioid antagonist is an amount effective for enhancing the potency of an opioid agonist for alleviating the chronic pain.
  • the pain intensity of the chronic pain is thereby alleviated (e.g., ameliorated, attenuated, reduced, diminished, blocked, inhibited or prevented).
  • an opioid antagonist or the combination of an opioid agonist and an opioid antagonist can each be administered at least once daily for at least one week, alternatively at least once daily for at least two weeks, at least once daily for at least three weeks, or at least once daily for a longer time.
  • the method for treating chronic pain, treating inflammation associated with a chronic condition, or treating an arthritic condition may comprise administering the opioid antagonist or each of the opioid agonist and the opioid antagonist no more than twice daily for at least one week, alternatively no more than twice daily for at least two weeks, alternatively no more than twice daily for at least three weeks, or no more than twice daily for a longer time.
  • the method for treating chronic pain, treating inflammation associated with a chronic condition, or treating an arthritic condition may comprise administering to the subject a daily amount of the opioid antagonist that is less than 0.004 mg, alternatively 0.002 mg or less.
  • compositions that comprise an opioid antagonist (e.g., an excitatory opioid receptor antagonist). Such compositions additionally preferentially comprise an opioid agonist (e.g., a bimodally-acting opioid agonist), and optionally a pharmaceutically acceptable carrier or excipient for administration to a subject, preferably a human, in need thereof. Such compositions optionally comprise an additional therapeutic agent.
  • opioid antagonist e.g., an excitatory opioid receptor antagonist
  • Such compositions optionally comprise an additional therapeutic agent.
  • the present methods and compositions may be employed for the treatment of inflammation associated with chronic conditions (including inhibiting progression of and/or reversing damage associated with inflammation), including the chronic conditions associated with inflammation in and around joints, muscles, bursae, tendons vertebrae, or fibrous tissue. Such methods and compositions provide reduced pain, reduced stiffness and/or improved physical function.
  • the present methods and compositions may be employed for the treatment of chronic conditions (including inhibiting progression of and/or reversing damage associated with chronic conditions).
  • Chronic conditions include, for example, arthritic conditions such as osteoarthritis, rheumatoid arthritis, and psoriatic arthritis.
  • the present methods and compositions may be used to treat one or more symptoms or signs of osteoarthritis of the joint, (such as a hip or knee) or the back (for example, the lower back).
  • Chronic conditions also include, for example, conditions associated with or resulting from pain such as chronic pain, including pain associated with or arising from cancer, from infection or from the nervous system (e.g., neurogenic pain such as peripheral neurogenic pain following pressure upon or stretching of a peripheral nerve or root or having its origin in stroke, multiple sclerosis or trauma, including of the spinal cord).
  • Chronic conditions also include, for example, conditions associated with or arising from psychogenic pain (e.g., pain not due to past disease or injury or visible sign of damage inside or outside the nervous system).
  • the present methods and compositions may also be employed for the treatment of other arthritic conditions, including gout and spondylarthropathris (including ankylosing spondylitis, Reiter's syndrome, psoriatic arthropathy, enterapathric spondylitis, juvenile arthropathy or juvenile ankylosing spondylitis, and reactive arthropathy).
  • the present methods and compositions may be used for the treatment of infectious or post-infectious arthritis (including gonoccocal arthritis, tuberculous arthritis, viral arthritis, fungal arthritis, syphlitic arthritis, and Lyme disease).
  • the present methods and compositions may be used for the treatment of arthritis associated with various syndromes, diseases, and conditions, such as arthritis associated with vasculitic syndrome, arthritis associated with polyarteritis nodosa, arthritis associated with hypersensitivity vasculitis, arthritis associated with Luegenec's granulomatosis, arthritis associated with polymyalgin rheumatica, and arthritis associated with joint cell arteritis.
  • arthritis associated with vasculitic syndrome arthritis associated with polyarteritis nodosa
  • arthritis associated with hypersensitivity vasculitis arthritis associated with Luegenec's granulomatosis
  • arthritis associated with polymyalgin rheumatica arthritis associated with joint cell arteritis.
  • compositions and methods herein include calcium crystal deposition arthropathies (such as pseudo gout), non-articular rheumatism (such as bursitis, tenosynomitis, epicondylitis, carpal tunnel syndrome, and repetitive use injuries), neuropathic joint disease, hemarthrosis, Henoch-Schonlein Purpura, hypertrophic osteoarthropathy, and multicentric reticulohistiocytosis.
  • calcium crystal deposition arthropathies such as pseudo gout
  • non-articular rheumatism such as bursitis, tenosynomitis, epicondylitis, carpal tunnel syndrome, and repetitive use injuries
  • neuropathic joint disease such as hemarthrosis, Henoch-Schonlein Purpura, hypertrophic osteoarthropathy, and multicentric reticulohistiocytosis.
  • compositions and methods herein include arthritic conditions associated with surcoilosis, hemochromatosis, sickle cell disease and other hemoglobinopathries, hyperlipo proteineimia, hypogammaglobulinemia, hyperparathyroidism, acromegaly, familial Mediterranean fever, Behat's Disease, lupus (including systemic lupus erythrematosis), hemophilia, and relapsing polychondritis.
  • arthritic conditions associated with surcoilosis, hemochromatosis, sickle cell disease and other hemoglobinopathries, hyperlipo proteineimia, hypogammaglobulinemia, hyperparathyroidism, acromegaly, familial Mediterranean fever, Behat's Disease, lupus (including systemic lupus erythrematosis), hemophilia, and relapsing polychondritis.
  • the methods and compositions for treating arthritic conditions, inflammation associated with chronic conditions or clironic pain alleviate (e.g., ameliorate, attenuate, reduce, diminish, block, inhibit or prevent) at least one symptom or sign of an arthritic condition, inflammation associated with a chronic condition, or chronic pain.
  • the methods and compositions may alleviate one or more of pain intensity, stiffness, or difficulty in physical functions.
  • the methods and compositions may attenuate one or more symptoms or signs of an arthritic condition, inflammation associated with a chronic condition, or chronic pain, wherein the sign or symptom after administration of the composition is ameliorated as compared to the sign or symptom before administration of the composition.
  • the present invention is directed to compositions, dosage forms, and kits with an opioid antagonist, including an opioid antagonist in combination with an opioid agonist, wherein the amount of the antagonist enhances the potency of an opioid agonist or wherein the amounts of the agonist and the amount of the antagonist together are effective to alleviate (e.g,, ameliorate, attenuate, reduce, diminish, block, inhibit or prevent) one or more symptoms or signs of an arthritic condition, inflammation associated with a clironic condition, or chronic pain.
  • the invention further relates to methods for administering to human subjects such compositions, dosage forms, and kits.
  • the present methods and materials may further comprise administering a pharmaceutically acceptable carrier or excipient for administration to the subject, preferably a human, in need thereof.
  • the present invention also provides methods for treating a subject with pain from an arthritic condition or inflammation associated with a chronic condition, comprising administering an amount of opioid antagonist effective to enhance the pain-alleviating potency of an opioid agonist, including an endogenous opioid agonist and optionally a pharmaceutically acceptable carrier or excipient for administration to the subject, preferably a human, in need thereof, whereby the pain is alleviated.
  • Such methods optionally include additionally administering an opioid agonist, and in such methods, the amount of antagonist is effective to enhance the pain-alleviating potency of the administered agonist.
  • the present invention also provides methods and materials for treating an arthritic condition or inflammation associated with chronic conditions.
  • the methods comprise administering to a human subject an amount of an opioid antagonist or the combination of an opioid agonist and an opioid antagonist that is effective to enhance potency of the agonist and/or to alleviate one or more symptoms or signs of an arthritic condition or inflammation associated with a chronic condition, including for example, as measured by a suitable index, scale or measure.
  • the attenuation of one or more symptoms or signs of an arthritic condition or of inflammation associated with a chronic condition may be measured on the WOMAC Osteoarthritis Index or one of its subscales (in other words, the pain, stiffness, or physical function subscales of the WOMAC Osteoarthritis Index).
  • WOMAC OA Index Any suitable version of the WOMAC OA Index may be used, including, for example, Version 3.0 or Version 3.1. Any suitable scale may be used as well.
  • the WOMAC OA Index is available in Likert and Visual Analog scaled formats, either of which may be employed in the present methods.
  • WOMAC values can be considered as surrogate markers for the diagnosis, prognosis, monitoring or treatment of an arthritic condition, inflammation from a chronic condition, and/or chronic pain.
  • the WOMAC values represent a subjective surrogate marker.
  • the attenuation of one or more symptoms or signs may be measured on another suitable index, scale or measure, such the Australian/Canadian (AUSCAN) Osteoarthritis Hand Index or the Osteoarthritis Global Index (OGI).
  • AUSCAN Australian/Canadian
  • OTI Osteoarthritis Hand Index
  • This measure which also may be designated as the ACR (American College of Rheumatology) 20 improvement, is a composite defined as both improvement of 20% in the number of tender and number of swollen joints, and a 20% improvement in three of the following five: patient global, physician global, patient pain, patient function assessment, and C- reactive protein (CRP).
  • CRP C- reactive protein
  • erythrocyte sedimentation rate ESR
  • joint tenderness score improvement by at least 2 grades on a 5-grade scale (or from grade 2 to grade 1) for patient and physician global assessments of current disease severity.
  • Current disease severity can be measured in a variety of ways, including patient or physician global assessments, patient or physician assessments of joint tenderness, joint swelling stiffness, pain, or physical function, • cytokine levels, B-cell or T-cell subtype ratios, erythrocyte sedimentation rate (ESR), or C- reactive protein.
  • Suitable measures of attenuation of one or more symptoms or signs, of inhibiting the progression of an arthritic condition or chronic condition, or of reversing tissue or cellular damage include measuring current disease severity.
  • the present invention provides methods and materials for alleviating pain associated with arthritic conditions or inflammation associated with chronic conditions.
  • the amount of an opioid antagonist or the combination of an opioid agonist and an opioid antagonist may be effective to enhance the potency of the agonist and/or to attenuate (e.g., ameliorate, alleviate, reduce, diminish, block, inhibit or prevent) (1) the pain felt by the subject when walking on a flat surface; (2) the pain felt by the subject when going up or down stairs; (3) the pain felt by the subject at night while in bed; (4) the pain felt by the subject that disturbs the sleep of the subject; (5) the pain felt by the subject while sitting or lying down; and/or (6) the pain felt by the subject while standing.
  • the present invention provides methods and materials for alleviating stiffness associated with arthritic conditions or inflammation associated with chronic conditions.
  • the amount of an opioid antagonist or the combination of an opioid agonist and an opioid antagonist may be effective to enhance the potency of the agonist and/or to attenuate (e.g., ameliorate, alleviate, reduce, diminish, block, inhibit or prevent) (1) the severity of the stiffness felt by the patient after the subject first woke up in the morning; (2) the severity of the stiffness felt by the subject after sitting or lying down later in the day; and/or (3) the severity of the stiffness felt by the subject while resting later in the day.
  • the present invention provides methods and materials for alleviating difficulty in physical function associated with arthritic conditions or inflammation associated with chronic conditions.
  • the amount of an opioid antagonist or the combination of an opioid agonist and an opioid antagonist may be effective to enhance the potency of the agonist and/or to attenuate (e.g., ameliorate, alleviate, reduce, diminish, block, inhibit or prevent) (1) the difficulty had by the subject when going down stairs; (2) the difficulty had by the human subject when going up stairs; (3) the difficulty had by the subject when getting up from a sitting position; (4) the difficulty had by the subject while standing; (5) the difficulty had by the subject when bending to the floor; (6) the difficulty had by the patient when walking on a flat surface; (7) the difficulty had by the human subject when getting in or out of a car or bus; (8) the difficulty had by the subject while going shopping; (9) the difficulty had by the patient when getting out of bed; (10) the difficulty had by the subject when putting on socks, or panty hose or stockings; (11) the difficulty had by the subject while lying in bed; (12) the difficulty had by the subject when getting in or out of the bathtub; (13) the difficulty had by the
  • Biomarkers have been identified, as described herein, that are useful in methods and materials for the treatment of an arthritic condition, inflammation from a chronic condition and/or clironic pain, including pain from an arthritic condition or inflammation.
  • a biomarker is a molecular entity, for example, a biochemical in the body, which has a molecular feature that makes it useful for diagnosis, prognosis, monitoring or treatment of a subject, including, for example, measuring progress of disease or effects of treatment.
  • Biomarkers can include inflammatory biomarkers.
  • An inflammatory biomarker can be any suitable biomarker known or recognized as being related to an inflammatory condition, including but not limited to: pro- inflammatory or anti-inflammatory, such as cytokines, mterleukin-1 through 17, including interleukin- l ⁇ (ILla), interleukin- l ⁇ (ILlb), IL2, IL4, IL5, IL6, IL8, IL10, IL13, tumor necrosis factor alpha (TNF ⁇ ), GM-CSF, interferon gamma (IFN- ⁇ ); markers of systemic inflammation, including, for example, CRP; certain cellular adhesion molecules such as e-selectin, integrins, ICAM-1, ICAM-3, BL-CAM, LFA-2, VCAM-1, NCAM, PECAM, and neopterin; and B61; leukotriene, thromboxane, isoprostane, serum amyloid A protein, fibrinectin, f ⁇ brinogen, leptin, pros
  • a sample that contains or may contain a biomarker can be obtained, including a biological sample.
  • Biological sample refers to a sample obtained from an organism (e.g., a human subject) or from components (e.g., cells, tissues or fluids) of an organism.
  • the sample can be a body fluid, tissue, or cell, including, but not limited to, blood, plasma, serum, blood cells (e.g., white cells), tissue or biopsy samples (e.g., tumor biopsy), urine, saliva, tears, sputum, synovial fluid, cerebrospinal fluid, peritoneal fluid, and pleural fluid, or cells therefrom.
  • An exemplary sample is a plasma sample.
  • Biological samples can also include sections of fluids, tissues or cells such as frozen sections taken for histological purposes.
  • Samples can be analyzed for the presence of biomarkers by a variety of methods.
  • Candidate biomarkers in such samples can include cytokines (e.g., objective biomarkers). Measurement of cytokines can be carried out in a number of ways known to those with skill in the art. Methods are available which can detect cytokines individually using traditional ELISA techniques (for example, Quantikine kits, available from R&D Systems, Minneapolis, Minnesota), or several cytokines can be detected simultaneously, using liquid or solid based array systems. For example, Luminex (Austin, Texas) has developed a liquid array system based on microspheres, wherein the spheres contain a mixture of two fluorophors.
  • the ratio of the two dyes within the mix is precisely controlled, and gives a unique spectral signature to 100 different species of the microbeads.
  • Each of these 100 different species is then coated with known and unique capture reagents, capable of interacting with molecules of interest within a complex mixture such as serum, plasma or cell culture supernatant.
  • These binder molecules can be entities such as antibodies, oligonucleotides, peptides and receptors.
  • a reporter molecule, specific for the analyte molecule of interest, is then used to quantitate binding.
  • the Luminex system requires a specific detector that uses microfluidics to detect individually labeled beads.
  • kits are available for use with this Luminex technology, including the Biosource International (Camarillo, California, www.biosource.com) human cytokine ten-plex antibody bead kit.
  • This kit measures members of two classes of cytokines, the TH1/TH2 and the inflammatory cytokines.
  • the TH1/TH2 set includes IL-2, -4, -5, -10, INF ⁇ while the inflammatory set is IL- 1 ⁇ , IL-6, IL-8, GMOCSF, and TNF ⁇ .
  • Linco (St. Charles, Missouri, www.lincoresearch.com) makes 13, 21, or 22-plex kits for cytokine measurement.
  • the 22-plex kit can simultaneously measure IL-l ⁇ , IL-l ⁇ , IL-2, -4, -5, -6, -7, -8, -10, -12p70, -13, -15, -17, Eotaxin, G-CSF,GM-CSF, IFN ⁇ , IP-10, MCP-1, MlP-l ⁇ , TNF ⁇ and RANTES.
  • cytokines including INF ⁇ , bFGF, GM-CSF, G-CSF, IL-2, -4, -5, -6, -8, -10, -17, IL-l ⁇ , IL-l ⁇ , IL-lra, TNF ⁇ , VEGF, ENA-78, MIP-1, MCP-1, RANTES, and Tpo.
  • Upstate (Charlottesville, Virginia, www.upstate.com) sells a variety of cytokine detection kits for use with the Luminex system that can detect up to 22 cytokines including IL-l ⁇ , IL-l ⁇ , IL-2, -3, -4, - 5, -6, -7, -8, -10, -12(p40), -12(p70), -13, -15, IP-10, Eotaxin, IFN ⁇ , GM-CSF, MCP-1, MlP-la, RANTES, and TNF ⁇ .
  • cytokine detection kits for use with the Luminex system that can detect up to 22 cytokines including IL-l ⁇ , IL-l ⁇ , IL-2, -3, -4, - 5, -6, -7, -8, -10, -12(p40), -12(p70), -13, -15, IP-10, Eotaxin, IFN ⁇ , GM-CSF, MCP-1, MlP-la, RANTES, and
  • Qiagen (Valencia, California, www.qiagen.com) sells a kit capable of detecting 11 analytes at once, including Eotaxin, MCP-1, RANTES, GM-CSF, INF ⁇ , IL-l ⁇ , IL- l ⁇ , IL- 2, -4, -5, -6, -8, 10, -12p70, and IL-13.
  • BIORAD Hercules, California, www.biorad.com
  • kits that can detect up to 17 cytokines at once, including : IL-l ⁇ , LL-2, -4, -5, -6, -7, -8, -10, -12p70, -13, -17, G-CSF, GM-CSF, INF ⁇ , MCP-1, MlP-l ⁇ , and TNF ⁇ .
  • kits that can detect up to 17 cytokines at once, including : IL-l ⁇ , LL-2, -4, -5, -6, -7, -8, -10, -12p70, -13, -17, G-CSF, GM-CSF, INF ⁇ , MCP-1, MlP-l ⁇ , and TNF ⁇ .
  • Luminex Hercules, California, www.biorad.com
  • kits for detecting several (1- 7) analytes at once and examples of these kits are the human TH1/TH2 kit that measures IL-2, -4, -6, 10, TNF ⁇ and LNF ⁇ , or the human inflammation kit which measures ILl ⁇ , IL6, IL8, IL10, TNF ⁇ and IL12p70.
  • Bender MedSystems (Vienna, Austria, www.bendermedsystems.com) has developed a product line, the FlowCytomix system, for use with flow cytometer that consists of microbeads coated with antibodies which will interact with various cytokines.
  • the beads are of varying sizes and have unique spectral qualities due to varying amounts of an internal fluorescent dye, and these properties allow the identification of each type of beads within a mixture of beads.
  • Bender MedSystems 's multicytokine kit measures several cytokines at once, and those to choose from include LNF ⁇ , ILl ⁇ , IL-2, -4, -5, -6, -8, -12, MCP-1, TNF ⁇ . Bender also sells a TH1/TH2 kit which measures human IL-l ⁇ , IL-2, -4, -5, -6, -8, -10, TNF ⁇ , TNF ⁇ and INF ⁇ simultaneously.
  • mini array ELISA systems have been used which measure seven different cytokines, TNF- ⁇ , IFN ⁇ , IFN ⁇ , IL-l ⁇ , IL-l ⁇ , IL-6, and IL-10 (see Moody et al, BioTechniques 31:186-194 (July 2001)).
  • Biochips have been developed for cytokine measurement (see Huang et al, CANCER RESEARCH 62, 2806-2812, May 15, 2002) wherein 43 cytokines can be detected including GM-CSF, G-CSF, IL-l ⁇ , IL-l ⁇ , IL-2, -3, -4, -5, 6, -8, -10, -12, -13, TNF ⁇ and VEGF.
  • cytokine measurement see Huang et al, CANCER RESEARCH 62, 2806-2812, May 15, 2002
  • 43 cytokines can be detected including GM-CSF, G-CSF, IL-l ⁇ , IL-l ⁇ , IL-2, -3, -4, -5, 6, -8, -10, -12, -13, TNF ⁇ and VEGF.
  • Array systems on glass slides have been developed (Tarn et al.
  • cytokines capable of measuring eight cytokines including INF ⁇ , IL-2, -4, -5, -6, -10 and -13 and TNF ⁇ ), or rolling circle amplified- antibody arrays which can measure up to 75 cytokines simultaneously (Schweitzer et al, Nature Biotechnology 20: 359- 365 (2002)) including IL-l ⁇ , IL-l ⁇ , IL-2, -4, -5, -6, -8, 10, -12, TNF ⁇ , RANTES and VEGF.
  • cytokines including INF ⁇ , IL-2, -4, -5, -6, -10 and -13 and TNF ⁇
  • rolling circle amplified- antibody arrays which can measure up to 75 cytokines simultaneously (Schweitzer et al, Nature Biotechnology 20: 359- 365 (2002)) including IL-l ⁇ , IL-l ⁇ , IL-2, -4, -5, -6, -8, 10, -12, TNF ⁇ , RANTES and VEGF.
  • Anti-cytokine arrays can be prepared in this system, making use of paired antibodies sets such as for example, C tosets, available from BioSource International.
  • a commercial human Thl/Th2 cytokine canvas is available from Pointilliste and was used as described in Example 4.
  • One or more cytokines can be employed as biomarkers for treatment using methods and materials as described herein.
  • one or more cytokines can be employed as a biomarker for treatment of an arthritic condition, inflammation associated with a chronic condition, and/or chronic pain, including pain from an arthritic condition or inflammation.
  • One or more cytokines can be used as a biomarker of the existence or extent (e.g., diagnosis, prognosis, monitoring) of an arthritic condition, of inflammation associated with a chronic condition, and or of chronic pain, including pain from arthritic conditions or inflammation.
  • one or more cytokines can be used as a biomarker to assess the treatment of an arthritic condition, inflammation associated with a chronic condition, and/or chronic pain, including pain from an arthritic condition or inflammation.
  • Examples of cytokines contemplated for such use as biomarkers include ILl ⁇ , ILl ⁇ , IL2, IL4, IL5, IL6, IL10, IL13, GM-CSF, interferon- ⁇ and TNF ⁇ .
  • the cytokines TNF ⁇ , IL6, IL4, and/or are used as biomarkers.
  • Cytokines can be measured as biomarkers before, during and/or after the administration of an opioid agonist, an opioid antagonist, or a combination of an opioid antagonist and opioid agonist.
  • cytokines When cytokines are to be employed as biomarkers for a subject, one or more cytokine levels for that subject are measured. Cytokines can be employed as biomarkers, for example, for monitoring, diagnosing, prognosing and/or treating the subject, including but not limited to selecting dose amounts and/or dosing regimens of an opioid antagonist alone or in combination with an opioid agonist.
  • Level(s) of one or more cytokines can be measured in a subject at risk for, or seeking, for example, diagnosis, prognosis, monitoring and/or treatment of, or reporting, one or more signs or symptoms of, an arthritic condition, inflammation associated with a chronic condition, and/or chronic pain, including pain from an arthritic condition or inflammation.
  • an appropriate treatment can be selected and administered.
  • the measured cytokine level(s) can be used to determine whether and how much opioid agonist and/or opioid antagonist are administered.
  • the dose amount and/or dosing regimen of an opioid agonist, an opioid antagonist, or a combination of an opioid antagonist and opioid agonist can be selected based upon the measured cytokine level(s). For example, if one or more of the measured cytokine levels is above a value, a physician can choose to treat a subject by administering an opioid agonist, an opioid antagonist, or a combination of opioid antagonist and opioid agonist.
  • the value can be a predetermined value or a value detennined at the time of or after measurement of the cytokine level(s).
  • a physician can select a higher or lower amount of opioid agonist and/or a higher or lower amount of antagonist for administration.
  • a more frequent or less frequent dosing regimen can be selected based on the measured cytokine level(s). For example, if the level of cytokines are higher than desired, an opioid antagonist can be dosed more frequently, or if the level of cytokines are lower than desired, an opioid antagonist can be dosed less frequently.
  • Level(s) of one or more cytokines can be measured for a subject who has already received or who is receiving treatment for an arthritic conditions, inflammation associated with a chronic condition, and/or chronic pain, including pain from an arthritic condition or inflammation.
  • the measured cytokine level(s) can be used to determine whether appropriate amounts and regimens have been or are being employed for treating the subject.
  • level(s) of one or more cytokines can be measured in a subject receiving treatment for an arthritic condition, inflammation associated with a chronic condition, and/or chronic pain, including pain from an artliritic condition or inflammation.
  • the treatment can be adjusted by administering a greater or lesser amount of an opioid agonist, an opioid antagonist, or a combination of opioid antagonist and opioid agonist and/or by altering the dosing regimen.
  • the value can be a predetermined value or a value determined at the time of or after measurement of the cytokine level(s).
  • Concentrations of cytokines can be used as biomarkers in adjusting the administration of an opioid antagonist to a subject.
  • a single cytokine concentration can be selected to evaluate whether a subject is in need of treatment. As an example, if a subject has a plasma concentration of TNF ⁇ which is higher than about 0.08 ng/ml, alternatively higher than 0.2 ng/ml, the subject is administered more opioid antagonist and/or more opioid agonist, by administering higher dose amounts and/or by administering on a more frequent dosing regimen.
  • the subject has a plasma concentration of TNF ⁇ which is about 0.08 ng/ml or lower, alternatively lower than 0.2 ng/ml, either the ao ⁇ ninistration of opioid antagonist is not changed, or the subject is administered less opioid antagonist and/or less opioid agonist, by administering lower dose amounts and/or by administering on a less frequent dosing regimen.
  • a subject has a plasma concentration of IL4 which is higher than about 0.23 ng/ml, the subject is administered more opioid antagonist and/or more opioid agonist, by administering higher dose amounts and/or by administering on a more frequent dosing regimen.
  • IL4 which is about 0.23 ng/ml or lower
  • either the administration of opioid antagonist is not changed, or the subject is administered less opioid antagonist and/or less opioid agonist, by administering lower dose amounts and/or by administering on a less frequent dosing regimen.
  • IL6 which is higher than about 0.18 ng/ml
  • the subject is administered more opioid antagonist and/or more opioid agonist, by administering higher dose amounts and/or by administering on a more frequent dosing regimen.
  • IL6 IL6
  • either the administration of opioid antagonist is not changed, or the subject is administered less opioid antagonist and/or less opioid agonist, by administering lower dose amounts and/or by administering on a less frequent dosing regimen.
  • One or more cytokine concentrations can be used as biomarkers in adjusting the administration of an opioid antagonist to a subject.
  • concentrations of ILl ⁇ , ILl ⁇ , IL2, IL4, IL5, IL6, IL10, IL13, GM-CSF, interferon- ⁇ and TNF ⁇ can be used to determine or adjust the treatment of an arthritic conditions, inflammation associated with a chronic condition, and/or chronic pain, including pain from an arthritic condition or inflammation.
  • E [Emaxl (Cp nl )/EC51 nl + Cp nl ] + [Emax2 (Cp n2 )/EC52 n2 + Cp n2 ] where the respective Emax values represent maximum effect for a given drug; EC51 and EC52 represent the potencies, for the drug notated as either 1 or 2, respectively (in other words, EC51 is not the concentration having 51% of the maximal effect, but rather EC51 is the concentration having a particular potency (e.g. 50% of the maximal effect for Effect No.
  • the Emax composite model is a recognized composite model for PK/PD data analysis set forth, for example, in Gabrielsson et al, PHARMACOKINETIC/PHARMACODYNAMIC DATA ANALYSIS: CONCEPTS AND APPLICATIONS, pp.
  • An effective amount to alleviate (e.g., ameliorate, attenuate, reduce, diminish, block, inhibit or prevent) symptom or sign of an arthritic condition or inflammation associated with chronic conditions refers to an amount of opioid antagonist or combination of opioid agonist and antagonist with or without one or more additional therapeutic agents which elicits alleviation (e.g., amelioration, attenuation, reduction, diminishment, blockage, inhibition or prevention) of at least one symptom or sign of an arthritic condition or inflammation associated with chronic conditions (e.g., pain) upon administration to a subject (e.g., patient) in need thereof.
  • the amount of the opioid agonist, the opioid antagonist, or another therapeutic agent can refer to the weight of the salt or the weight of the free base of such agonist, antagonist or agent.
  • An amount of opioid antagonist that enhances the potency to alleviate a sign or symptom, such as the potency to alleviate pain intensity, stiffness, or difficulty physical function, of opioid agonist is the amount that when added to an analgesic or subanalgesic amount of agonist results upon administration in a greater alleviation (e.g., amelioration, attenuation, reduction, diminishment, blockage, inhibition or prevention) of at least one sign or symptom, such as pain, stiffness, or difficulty in physical function, than the alleviation of that sign or symptom resulting from administration of that agonist alone (i.e., without that amount of antagonist).
  • An amount of opioid antagonist that enhances the potency of an endogenous opioid agonist is the amount that when administered alone or with opioid agonist or another therapeutic agent, results in a greater alleviation (e.g., amelioration, attenuation, reduction, diminishment, blockage, inhibition or prevention) of at least one sign or symptom of pain than the alleviation of that sign or symptom without that amount of antagonist.
  • Opioids refer to compounds or compositions, including metabolites of the compounds or compositions, that bind to specific opioid receptors and have agonist (activation) or antagonist (inactivation) effects at the opioid receptors.
  • Inhibitory opioid receptors refer to opioid receptors that mediate hihibitory opioid receptor functions, such as analgesia.
  • Opioid receptor agonist or opioid agonist refers to an opioid compound or composition, including any active metabolite of such compound or composition, that binds to and activates opioid receptors on neurons that mediate pain.
  • An opioid receptor antagonist or opioid antagonist refers to an opioid compound or composition, including any active metabolite of such compound or composition, that binds to and blocks opioid receptors on neurons that mediate pain.
  • An opioid antagonist attenuates (e.g., blocks, inhibits, prevents, or competes with) the action of an opioid agonist.
  • Pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • compositions refer to derivatives of the disclosed compounds wherein the compounds are modified by making at least one acid or base salt thereof, and includes inorganic and organic salts.
  • An analgesic amount refers of opioid agonist to an amount of the opioid agonist which causes analgesia in a patient administered the opioid receptor agonist alone, and includes standard doses of the agonist which are typically administered to cause analgesia (e.g. mg doses).
  • a subanalgesic amount of opioid agonist refers to an amount which does not cause analgesia in a patient administered the opioid receptor agonist alone, but when used in combination with a potentiating or enhancing amount of opioid antagonist, results in analgesia.
  • An effective antagonistic amount of opioid agonist refers to an amount that effectively attenuates (e.g. ameliorates, reduces, diminishes, blocks, inhibits, prevents, or competes with) the analgesic activity of an opioid agonist.
  • a therapeutically effective amount of a composition refers to an amount that elicits alleviation (e.g., amelioration, attenuation, reduction, diminishment, blockage, inhibition or prevention) of at least one sign or symptom of an arthritic condition, inflammation associated with a chronic condition, or clironic pain upon administration to a patient in need thereof.
  • alleviation e.g., amelioration, attenuation, reduction, diminishment, blockage, inhibition or prevention
  • Potency may refer to the strength of a drug or drug treatment in producing desired effects, for example, improved pain relief, improved pain control, reduced stiffness, and/or improved physical function. Potency also may refer to the effectiveness or efficacy of a drag treatment in eliciting desired effects, for example, improved pain relief, improved pain control, reduced stiffness, and/or improved physical function. For example, enhanced potency may refer to the lowering of a dose in achieving desired effects or to an increased therapeutic benefit including that not previously seen. In therapeutics, for example, potency may refer to the relative pharmacological activity of a compound or a composition.
  • the antagonist in the present compositions may be present in its original form or in the form of a pharmaceutically acceptable salt.
  • the antagonists in the present compositions include: naltrexone, naloxone, nalmefene, methylnaltrexone, methiodide, nalorphine, naloxonazine, nalide, nalmexone, nalorphine dinicotinate, naltrindole (NTI), naltrindole isothiocyanate, (NTII), naltriben (NTB), nor-binaltorphimine (nor-BNI), b-funaltrexamine (b-FNA), BNTX, cyprodime, ICI-174,864, LY 117413, MR2266, or an opioid antagonist having the same pentacyclic nucleus as nalmefene, naltrexone, levorphanol, meptazinol, dezocine, or their pharmacologically effective esters or salts.
  • Preferred opioid antagonists include naltrexone, nalmefene, naloxone, or mixtures thereof. Particularly preferred is nalmefene or naltrexone.
  • an opioid antagonist is provided in an amount from about 1 fg to about 1.0 mg or from about 1 fg to about 1 ⁇ g, including where the amount is provided by administration 1, 2, 3, or 4 times per day.
  • the opioid antagonist is provided in an amount from at least about 0.000001 mg to about or less than about 0.5 or 1.0 mg, 0.00001 mg to about or less than about 0.5 or 1.0 mg, 0.0001 mg to about or less than about 0.5 or 1.0 mg, or at least about 0.001 mg to about or less than about 0.5 or 1.0 mg, or at least about 0.01 mg to about or less than about 0.5 or 1.0 mg, or at least about 0.1 mg to about or less than about 0.5 or 1.0 mg.
  • Preferred ranges of opioid antagonists also include: from about 0.000001 mg to less than 0.2 mg; from about 0.00001 mg to less than 0.2 mg; from about 0.0001 mg to less than 0.2 mg; from about 0.001 mg to less than 0.2 mg; from about 0.01 mg to less than 0.2 mg; or from about 0.1 mg to less than 0.2 mg. Additional preferred ranges of opioid antagonists include: from about 0.0001 mg to about 0.1 mg; from about 0.001 mg to about 0.1 mg; from about 0.01 mg. to about 0.1 mg; from about 0.OO1 mg to about 0.1 mg; from about 0.001 mg to about 0.01 mg; or from about 0.01 mg to about 0.1 mg.
  • the maximum amount of antagonist is 1 mg, alternatively less than 1 mg, alternatively 0.99 mg, alternatively 0.98 mg, alternatively 0.97 mg, alternatively 0.96 mg, alternatively 0.95 mg, alternatively 0.94 mg, alternatively 0.93 mg, alternatively 0.92 mg, alternatively 0.91 mg, alternatively 0.90 mg, alternatively 0.89 mg, alternatively 0.88 mg, alternatively 0.87 mg, alternatively 0.86 mg, alternatively 0.85.
  • the maximum amount of antagonist in the dosage form is less than 0.5 mg, alternatively 0.49 mg, alternatively 0.48 mg, alternatively 0.47 mg, alternatively 0.46 mg, alternatively 0.45 mg, alternatively 0.44 mg, alternatively 0.43 mg, alternatively 0.42 mg, alternatively 0.41 mg, alternatively 0.40 mg, alternatively 0.39 mg, alternatively 0.38 mg, alternatively 0.37 mg, alternatively 0.36 mg, alternatively 0.35 mg, alternatively 0.34 mg, alternatively 0.33 mg, alternatively 0.32 mg, alternatively 0.31 mg, alternatively 0.30 mg, alternatively 0.29 mg, alternatively 0.28 mg, alternatively 0.27 mg, alternatively 0.26 mg, alternatively 0.25 mg, alternatively 0.24 mg, alternatively 0.23 mg, alternatively 0.22 mg, alternatively 0.21 mg, alternatively 0.20 mg, alternatively 0.19 mg, alternatively 0.18 mg, alternatively 0.17 mg, alternatively 0.16 mg, alternatively 0.15 mg, alternatively 0.14 mg, alternatively 0.13 mg, alternatively 0.12 mg, alternatively 0.11 mg,
  • the min ⁇ num amount of antagonist in the dosage form is 0.0001 mg, alternatively 0.0002 mg, alternatively 0.0003 mg, alternatively 0.0004 mg, alternatively 0.0005 mg, 0.0006 mg, alternatively O.0007 mg, alternatively 0.0008 mg, alternatively 0.0009 mg, alternatively 0.001 mg, alternatively 0.002 mg, alternatively 0.003 mg, alternatively 0.004 mg, alternatively 0.005 mg, alternatively 0.006 mg, alternatively 0.007 mg, alternatively 0.008 mg, alternatively 0.009 mg, alternatively 0.01 mg, alternatively 0.011 mg, alternatively 0.012 mg, alternatively 0.013 mg, alternatively 0.014 mg, alternatively 0.015 mg, alternatively 0.016 mg, alternatively 0.017 mg, alternatively 0.018 mg, alternatively 0.019 mg, alternatively 0.02 mg, alternatively 0.021 mg, alternatively 0.022 mg, alternatively 0.023 mg, alternatively 0.024 mg, alternatively 0.025 mg, alternatively 0.026 mg, alternatively
  • the maximum amount of antagonist is less than 0.0020 mg, alternatively 0.0019 mg, alternatively 0.0018 mg, alternatively 0.0017 mg, alternatively 0.O016 mg, alternatively 0.0015 mg, alternatively 0.0014 mg, alternatively 0.0013 mg, alternatively 0.0012 mg, alternatively 0.0011 mg, alternatively 0.0010 mg, alternatively 0.0009 mg, alternatively 0.0008 mg, alternatively 0.0007 mg, alternatively 0.0006 mg, alternatively 0.O005 mg, alternatively 0.0004 mg, alternatively 0.0003 mg, alternatively 0.0002 mg, alternatively 0.0001 mg.
  • the minimum amount of antagonist in the preferred dosage form is O.0001 mg, alternatively 0.0002 mg, alternatively 0.0003 mg, alternatively 0.0004 mg, alternatively 0.0005 mg, alternatively 0.0006 mg, alternatively 0.0007 mg, alternatively 0.0008 mg, alternatively 0.0009 mg, alternatively 0.0010 mg, alternatively 0.0011 mg, alternatively 0.O012 mg, alternatively 0.0013 mg, alternatively 0.0014 mg, alternatively 0.0015 mg, alternatively 0.0016 mg, alternatively 0.0017 mg, alternatively 0.0018 mg, alternatively 0.0019 mg, alternatively 0.002 mg.
  • any minimum amount and any maximum amount of antagonist in the dosage form, as specified above, may be combined to define a range of amounts, providing that the minimum selected is equal to or less than the maximum selected.
  • the amount of an opioid antagonist in the compositions for use in methods according to the present invention effective to enhance the potency of an opioid agonist can be less than an effective antagonistic amount.
  • the effective amount of an opioid antagonist in the present compositions can be about 0.002 mg.
  • the effective amount of an opioid antagonist in the present compositions can be less than 0.002 mg.
  • the effective amount of an opioid antagonist in the present compositions can be about 0.001 mg. .
  • the effective amount of an opioid antagonist in the present compositions can be less than 0.001 mg.
  • the effective amount of an opioid antagonist in the present compositions can be more than 0.0001 mg.
  • the effective amount of an opioid antagonist in the present compositions can be about 0.0001 mg.
  • the effective amount of an opioid antagonist in the present compositions can be about 0.00001 mg.
  • the effective amount of an opioid antagonist in the present compositions can be less than 0.00001 mg.
  • the effective amount of an opioid antagonist in the present compositions can be more than 0.00001 mg.
  • the effective amount of an opioid antagonist in the present compositions can be about 0.000001 mg.
  • the effective amount of an opioid antagonist in the present compositions can be less than 0.000001 mg.
  • the effective amount of an opioid antagonist in the present compositions can be more than 0.000001 mg.
  • any of the foregoing effective amounts may be administered one time per day, alternatively two times per day, alternatively three times per day, alternatively four times per day.
  • any of the followmg effective amounts may be divided over a series of dosages within one day or other relevant time period.
  • the effective amount may be divided into one, two, three or four doses administered over the day or other time period.
  • Preferred effective amounts of an opioid antagonist include a total daily dose from about 0.00002 mg to about 0.002 mg, wherein the total daily dose is divided into 1, 2, 3, or 4 doses.
  • the opioid antagonist in preferably in an amount from about 0.00001 mg to about 0.001 mg in each of the two doses.
  • the opioid antagonist in an amount from about 0.00002 mg to about 0.002 mg in the dose.
  • the opioid antagonist in an amount from about 0.000005 mg to about 0.0005 mg in each of the four doses.
  • the agonist may be present in its original form or in the form of a pharmaceutically acceptable salt.
  • the agonists for use in methods according to the present invention include: alfentanil, allylprodine, alphaprodine, anileridine, apomorphine, apocodeine, benzy norphine, bezitramide, butorphanol, clonitazene, codeine, cyclazocine, cyclorphen, cyprenorphine, desomorphine, dextromoramide, dezocine, dia promide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxyaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmo hine, etonitazene, fentanyl, heroin, hydrocodone, hydroxymethylmorphinan, hydromorphone, hydroxypethidine, isomethadone
  • Preferred agonists for use in methods according to the present invention are morphine, hydrocodone, oxycodone, codeine, fentanyl (and its relatives), hydromorphone, meperidine, methadone, oxymorphone, propoxyphene or tramadol, or mixtures thereof.
  • Particularly preferred contemplated agonists are morphine, hydrocodone, oxycodone or tramadol.
  • Opioid agonists include exogenous or endogenous opioids.
  • Endogenous opioid agonists include endorphin, beta-endorphin, enkephalin, met- enkephalin, dynorphin, orphanin FQ, neuropeptide FF, nociceptin, endomorphin, endormorphin- 1, endormorphin-2.
  • the agonist may be present in an amount that is analgesic or subanalgesic (e.g., non- analgesic) in the human subject.
  • the agonist is administered in dosage forms containing from about 0.1 to about 300 mg of agonist, alternatively from about 2.5 to about 160 mg of agonist.
  • the agonist, in conjunction with antagonist is included in the dosage form in an amount sufficient to produce the desired effect upon the process or condition of pain, including inflammatory pain, such as alleviation (e.g., amelioration, attenuation, reduction, diminishment, blockage, inhibition or prevention) of at least one symptom of pain, including inflammatory pain.
  • Symptoms and signs include, for example, pain (including chronic pain), stiffness or difficulty in physical function.
  • Preferred combinations of an opioid antagonist and opioid agonist in the present compositions are naltrexone and oxycodone; naltrexone and oxymorphone; naltrexone and hydrocodone; naltrexone and hydromorphone; naltrexone and morphine; nalmefene and oxycodone; nalmefene and oxymorphone; nalmefene and hydrocodone; nalmefene and hydromorphone; nalmefene and mo ⁇ phine; naloxone and oxycodone; naloxone and oxymorphone; naloxone and hydrocodone; naloxone and hydromorphone; and naloxone and morphine, respectively.
  • the more preferred combinations of an opioid antagonist and opioid agonist in the present compositions are naltrexone and oxycodone; naltrexone and oxymorphone; naltrexone and hydrocodone; naltrexone and hydromorphone; naltrexone and morphine; nalmefene and oxycodone; nalmefene and oxymorphone; nalmefene and hydrocodone; nalmefene and hydromorphone; and nalmefene and morphine, respectively.
  • the most preferred combinations of an opioid antagonist and opioid agonist in the present compositions are naltrexone and oxycodone; naltrexone and oxymorphone; naltrexone and hydrocodone; naltrexone and hydromorphone; and naltrexone and morphine, respectively.
  • the amount of antagonist in the dosage form is less than an effective amount to antagonize an exogenous or endogenous agonist, but such an amount is effective to enhance the pain-enhancing potency, including the inflammatory pain-enhancing potency, of the agonist and optionally but preferably is effective to attenuate an adverse effect of the agonist, for example, tolerance, withdrawal, dependence and/or addiction.
  • the method further comprises administering the opioid agonist, in either a combined dosage form with the antagonist or in a separate dosage form.
  • Still another aspect of the invention provides an immediate release solid oral dosage form comprising one or more pharmaceutical excipients, a dose of an opioid agonist and a low dose of an opioid antagonist, wherein the opioid agonist and opioid antagonist are release concurrently when placed in an aqueous environment.
  • the opioid antagonist and opioid agonist can be formulated as immediate release, (IR), controlled release (CR) and/or sustained released (SR) formulations. Formulations can have components that are combinations of IR and/or CR and/or SR components.
  • the combination dosage forms of the present compositions can be formulated to provide a concurrent release of the opioid antagonist in combination with opioid agonist and/or other therapeutic agent generally throughout at least a majority of the delivery profile for the formulation.
  • the terms “concurrent release” and “released concurrently” mean that the agonist and antagonist are released in in vitro dissolution assays in an overlapping manner.
  • the respective beginnings of release of each agent can but need not necessarily be simultaneous. Concurrent release will occur when the majority of the release of the first agent overlap a majority of release of the second agent.
  • a desired portion of each active pharmaceutical ingredient may be released within a desired time.
  • the desired portions may be, for example, 5%, 50% or 90%, or some other percentage between 1% and 100%.
  • the desired time may be in minutes or hours, for example, 10 minutes, 20 minutes, 30 minutes, or 45 minutes, or some other time.
  • the desired portion and the desired time may be varied by the inclusion of formulants for the controlled release or sustained release of any therapeutic agent(s).
  • the optimum amounts of the opioid antagonist administered in combination with an opioid agonist or other therapeutic agent will of course depend upon the particular antagonist and agonist or other agent used, the excipient chosen, the route of administration, and/or the pharmacokinetic properties of the patient being treated. Effective administration levels of antagonist and agonist or other agent will vary upon the state and circumstances of the patient being treated. As those skilled in the art will recognize, many factors that modify the action of an active ingredient will be taken into account by a treating physician, such as the age, body weight, sex, diet, and condition of the patient, the lapse of time between the condition or injury and the administration of the present compositions, and the administration technique. A person of ordinary skill in the art will be able to ascertain the optimal dosage for a given set of conditions in view of the disclosure herein.
  • the opioid agonist and/or antagonist can be present in the present compositions as an acid, base, pharmaceutically acceptable salt, or a combination thereof.
  • the pharmaceutically acceptable salt embraces inorganic or organic salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts made, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfonic, sulfamic, phosphoric, nitric and others known to those skilled in the art; and the salts prepared from organic acids such as amino acids, acetic, propionic, succinic, glycolic, stearic, lactic, malic, malonic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, glucuronic, and other acids.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfonic, sulfamic, phosphoric, nitric and others
  • salts and variants include mucates, phosphate (dibasic), phosphate (monobasic), acetate trihydrate, bi(heptafluorobutyrate), bi(methylcarbamate), bi ⁇ entafluoropropionate), mesylate, bi(pyridine-3-carboxylate), bi(trifluoroacetate), bitartrate, chlorhydrate, and sulfate pentahydrate.
  • the salt may include an amine-based (primary, secondary, tertiary or quaternary amine) counter ion, an alkali metal cation, or a metal cation.
  • amine-based (primary, secondary, tertiary or quaternary amine) counter ion an alkali metal cation, or a metal cation.
  • suitable salts are found in texts such as Remington's Pharmaceutical Sciences, 18 th Ed. (Alfonso R. Gennaro, ed.; Mack Publishing Company, Easton, PA, 1990); Remington: the Science and Practice of Pharmacy 19 th Ed.( Lippincott, Williams & Wilkins, 1995); Handbook of Pharmaceutical Excipients, 3 r Ed. (Arthur H. Kibbe, ed.; Amer. Pharmaceutical Assoc, 1999); the Pharmaceutical Codex: Principles and Practice of Pharmaceutics 12 Ed.
  • Additional representative salts include hydrobromide, hydrochloride, mucate, succinate, n-oxide, sulfate, malonate, acetate, phosphate dibasic, phosphate monobasic, acetate trihydrate, bi(heplafluorobutyrate), maleate, bi(methylcarbamate), bi ⁇ entafluoropropionate), mesylate, bi ⁇ yridine-3-carboxylate), bi(trifluoroacetate), bitartrate, chlorhydrate, fumarate, and sulfate pentahydrate.
  • the methods may further comprise administering to the subject another therapeutic agent, for example, non-steroidal anti-inflammatory drug agents or local anesthetic and/or analgesic agents, TNF-o antagonists, corticosteroids, disease-modifying anti-rheumatic drugs (DMARDs), anticonvulsant agents, tricyclic antidepressant agents, anti-dyno ⁇ hin agents, glutamate receptor antagonist agents, hi particularly, it is specifically completed that, in addition to the opioid agonist and the opioid antagonist, the subject may be administered TNF- ⁇ antagonists, P38 inhibitors, and cytokines inhibitors (including but not limited to IL-2, IL-6, IL- 8, and GM-CSF).
  • another therapeutic agent for example, non-steroidal anti-inflammatory drug agents or local anesthetic and/or analgesic agents, TNF-o antagonists, corticosteroids, disease-modifying anti-rheumatic drugs (DMARDs), anticonvulsant agents, tricyclic antidepressant agents, anti-dyno
  • An NSAID refers to a non-steroidal anti-inflammatory drug and includes anti- inflammatory drugs such as aspirin, members of the cycloxgenease I, II and III inl ibitors, and includes naproxen sodium, diclofenac and misoprostol, valdecoxib, diclofenac, celecoxib, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, meloxicam, ibuprofen, naproxen, mefenamic acid, nabumetone, ketorolac, chorine or magnesium salicylates, rofecoxib, tolmetin sodium, phenylbutazone, oxyphenbutzone, meclofenamate sodium or diflusenal.
  • anti- inflammatory drugs such aspirin, members of the cycloxgenease I, II and III inl ibitors, and includes naproxen sodium, diclofenac and misopros
  • the present compositions further comprise at least one non-narcotic analgesic, such as a nonsteroidal anti-inflammatory agent (NSAID).
  • NSAID nonsteroidal anti-inflammatory agent
  • Representative nonsteroidal anti-inflammatory agents include aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxican, sulindac, tolmetin, and zomepirac.
  • NSAIDs include Celebrex ® , Nioxx ® , Anaprox ® , Artl rotec ® , Bextra ® , Cataflam ® , Clinoril ® , DayPro ® , Dolobid ® , Feldene ® , Indocin ® , Mobic ® , Motrin ® , Negprelen ® , Naprosyn ® , Ponstel ® , Relafen ® , Toradol ® .
  • the present compositions may further comprise an analgesic, antipyretic, and/or anti-inflammatory therapeutic agent.
  • the composition may further comprise one or more of aspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal, sulfasalazine, olsalazine, acetaminophen, indomethacin, sulindac, tolmetin, diclofenac, ketorolac, ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen, oxaprozin, mefenamic acid, meclofenamic acid, piroxicam, meloxicam, nabumetone, refecoxib, celecoxib, etodolac, and nimesulide.
  • the non-narcotic analgesic is present in a inflammatory pain-alleviating amount or an amount that is not pain-alleviating alone but is pain-alleviating in combination with an opioid agonist and opioid antagonist according to the invention.
  • This amount is at a level corresponding to the generally recommended adult human dosages for a particular non-narcotic analgesic.
  • the effective inflammatory pain-alleviating amount of the opioid antagonist and the opioid agonist can be present at a level that potentiates the inflammatory pain-alleviating effectiveness of the non-narcotic analgesic.
  • the present compositions further comprise at least one inhibitor of TNF- ⁇ .
  • Inhibitors of TNF- ⁇ may also be designated TNF- ⁇ antagonists.
  • TNF- ⁇ antagonists are compounds which are capable of, directly or indirectly, counteracting, reducing or inl ibiting the biological activity of TNF- ⁇ , or the activation of receptors therefore.
  • Tumor necrosis factor (TNF) is a key proinflammatory cytokine released by a number of cell types, particularly activated macrophages and monocytes. Two forms of TNF are released — TNF- ⁇ and TNF-beta.
  • TNF- ⁇ is a soluble homotrimer of 17 kD protein subunits (Smith et al., J. Biol. Chem.
  • TNF- ⁇ antagonist can be a compound that affects the synthesis of TNF- ⁇ , or one that affects the maturation of TNF- ⁇ , or one that inhibits the binding of TNF- ⁇ with a receptor specific for TNF- ⁇ , or one that interferes with intracellular signaling triggered by TNF ⁇ binding with a receptor. Additional details regarding the manufacture and use of TNF- ⁇ antagonists are available in U.S. Patent Application Publication No. US 2003/0157061 Al, which is inco ⁇ orated herein by reference.
  • Preferred TNF- ⁇ antagonists for the present invention include ENBREL ® (etanercept) from Wyeth-Ayerst Laboratories/Immunex; REMICADE ® , infiximab, which is an anti-TNF chimeric Mab (Centocor; Johrxson& Johnson); anti- TNF- ⁇ , D2E7 human Mab (Cambridge antibody Technology); CDP-870, which is a PEGylated antibody fragment (Celltech); CDP-571; Humicade, which is a humanized Mab described in U.S. Pat. No.
  • TNF- ⁇ Receptor- 1 5,994,510 (Celltech); PEGylated soluble TNF- ⁇ Receptor- 1 (Amgen); TBP-1, which is a TNF binding protein (Ares Serono); PASSTNF-alpha ® , which is an anti-TNF- ⁇ polyclonal antibody (Verigen); AGT-1, which is a mixture of three anti-cytokine antibodies to IFN-alpha, IFN-gamma, and TNF (Advanced Biotherapy Concepts); TENEFUSE ® , ienercept, which is a TNFR-Ig fusion protein (Roche); CytoTAB ® (Protherics); TACE, which is a small molecule TNF- ⁇ converting enzyme inhibitor ( nmunex); small molecule TNF mRNA synthesis inhibitor (Nereus); PEGylated p75TNFR Fc utein (Immunex); and TNF- ⁇ antisense inhibitor.
  • TBP-1 TNF binding
  • the TNF- ⁇ antagonist is present at an amount effective to inhibit progression or reduce damage from an arthritic condition or a chronic condition associated with inflammation.
  • the TNF- ⁇ antagonist is present in an amount that is not effective to inhibit progression or reduce damage alone but is effective to inhibit progression or reduce damage in combination with an opioid agonist and opioid antagonist according to the invention. This amount is at a level corresponding to the generally recommended adult human dosages for a particular TNF- ⁇ antagonist.
  • the effective pain- alleviating amount of the opioid antagonist and the opioid agonist can be present at a level that potentiates the effectiveness of a TNF- ⁇ antagonist.
  • TNF- ⁇ antagonists that can be used herein as given, inter alia, axe included, for example, in the "Physicians' Desk Reference", 2003 Edition (Medical Economics Data Production Company, Montvale, NJ.) as well as in other reference works including Goodman and Gilman's "The Pharmaceutical Basis of Therapeutics” and “Remington's Pharmaceutical Sciences,” the disclosure of all are inco ⁇ orated herein by reference.
  • the dosage level of the TNF- ⁇ antagonist there can be a wide variation in the dosage level of the TNF- ⁇ antagonist, wherein the dosage level depends to a large extent on the specific TNF- ⁇ antagonist being administered. These amounts can be detennined for a particular drag combination, in accordance with this invention, by employing routine experimental testing.
  • the present compositions further comprise at least one anti- rheumatic drug.
  • Anti-rheumatic drags include those referred to as Disease-modifying antirheumatic drugs (DMARDs).
  • Anti-rheumatic drags include methotrexate (RHEUMATREX, TREXALL), leflunomide (ARANA), D-Penicillamine, sulfasalazine, gold therapy, minocycline, azathioprine, hydroxychloroquine (PLAQUE ⁇ IL) and other antimalarials, cyclosporine and biologic agents.
  • Biologic response modifiers often referred to as biologic agents or simply biologies, are designed to either inhibit or supplement immune system components called cytokines.
  • Cytokines play a role in either fueling or suppressing the inflammation that causes damage in RA and some other diseases.
  • Anakinra KI ⁇ ERET blocks the action of the cytokine interleukin- 1 (IL-1).
  • the anti-rheumatic drug is present at an amount that attenuates a symptom or sign of rheumatism or an amount that does not attenuate such a symptom or sign alone but does attenuate such a symptom or sign in combination with an opioid agonist and opioid antagonist according to the invention.
  • This amount is at a level corresponding to the generally recommended adult human dosages for a particular anti-rheumatic drug.
  • the effective amount of the opioid antagonist and the opioid agonist can be present at a level that potentiates the effectiveness of the anti-rheumatic drug.
  • the present compositions further comprise at least one anticonvulsant or anti-epileptic agent.
  • Any therapeutically effective anticonvulsant may be used according to the invention.
  • anticonvulsants see, e.g., Goodman and Gilman's "The Pharmaceutical Basis Of Therapeutics” , 8th ed., McGraw-Hill, Inc. (1990), pp. 436-462, and "Remington's Phannaceutical Sciences", 17th ed., Mack Publishing Company (1985), pp. 1075-1083 (the disclosures of which are inco ⁇ orated herein by reference).
  • anticonvulsants that can be used herein include lamotrigine, gabapentin, valproic acid, topiramate, famotodine, phenobarbital, diphenylhydantoin, phenytoin, mephenytoin, ethotoin, mephobarbital, primidone, carbamazepine, ethosuximide, methsuximide, phensuximide, trimethadione, benzodiazepine, phenacemide, acetazolamide, progabide, clonazepam, divalproex sodium, magnesium sulfate injection, metharbital, paramethadione, phenytoin sodium, valproate sodium, clobazam, sulthiame, dilantin, diphenylan and L-5- hydroxytryptophan.
  • the anticonvulsant is present at a pain-alleviating amount or an amount that is not pain-alleviating alone but is pain-alleviating in combination with an opioid agonist and opioid antagonist according to the invention. This amount is at a level corresponding to the generally recommended adult human dosages for a particular anticonvulsant.
  • the effective pain-alleviating amount of the opioid antagonist and the opioid agonist can be present at a level that potentiates the pain-alleviating effectiveness of the anticonvulsant.
  • Specific dosage levels for anticonvulsants that can be used herein as given, inter alia, are included, for example, in the "Physicians' Desk Reference", 2003 Edition (Medical Economics Data Production Company, Montvale, NJ.) as well as in other reference works including Goodman and Gilman's "The Pharmaceutical Basis of Therapeutics" and “Remington's Pharmaceutical Sciences,” the disclosure of all are inco ⁇ orated herein by reference.
  • compositions presented herein may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable excipients, carriers, diluents or other adjuvants.
  • excipients for example, pharmaceutically acceptable sulfate, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, EDTA, FD&T, FD&T, FD&T, FD&T, FD&T, FD&T, FD&T, FD&T, FD&T, FD&T, FD&T, FD&T, FD&T, FD&T, FD&T, FD&T, FD&T, FD&T, FD&T, FD&T, FD&T, FD&T, FD
  • the excipients, binders, carriers, and diluents which can be used include water, glucose, lactose, natural sugars such as sucrose, glucose, or corn sweeteners, sorbitol, natural and synthetic gums such as gum acacia, tragacanth, sodium alginate, and gum arabic, gelatin, mannitol, starches such as starch paste, corn starch, or potato starch, magnesium trisilicate, talc, keratin, colloidal silica, urea, stearic acid, magnesium stearate, dibasic calcium phosphate, crystalline cellulose, methyl cellulose, carboxymethyl cellulose, polyethylene glycol, waxes, glycerin, and saline solution, among others.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.
  • the dosage forms can also comprise one or more acidifying agents, adsorbents, alkalizing agents, antiadherents, antioxidants, binders, buffering agents, colorants, complexing agents, diluents or fillers, direct compression excipients, disintegrants, flavorants, fragrances, glidants, lubricants, opaquants, plasticizers, polishing agents, preservatives, sweetening agents, or other ingredients known for use in pharmaceutical preparations.
  • acidifying agents adsorbents, alkalizing agents, antiadherents, antioxidants, binders, buffering agents, colorants, complexing agents, diluents or fillers, direct compression excipients, disintegrants, flavorants, fragrances, glidants, lubricants, opaquants, plasticizers, polishing agents, preservatives, sweetening agents, or other ingredients known for use in pharmaceutical preparations.
  • Acidifying agents are a compound used to provide an acidic medium for product stability. Such compounds include, by way of example and without limitation, acetic acid, amino acid, citric acid, fumaric acid and other alpha hydroxy acids, hydrochloric acid, ascorbic acid, nitric acid, phosphoric acid, and others known to those skilled in the art.
  • Adsorbents are agents capable of holding other molecules onto their surface by physical or chemical (chemiso ⁇ tion) means.
  • Such compounds include, by way of example and without limitation, powdered and activated charcoal, zeolites, and other materials known to one of ordinary skill in the art.
  • Alkalizing agent are compounds used to provide an alkaline medium for product stability. Such compounds include, by way of example and without limitation, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium bicarbonate, sodium hydroxide, triethanolamine, and trolamine and others known to those skilled in the art.
  • Antiadherent are agents that prevents the sticking of solid dosage formulation ingredients to punches and dies in a tableting machine during production.
  • Such compounds include, by way of example and without limitation, magnesium stearate, talc, calcium stearate, glyceryl behenate, PEG, hydrogenated vegetable oil, mineral oil, stearic acid and other materials known to one of ordinary skill in the art.
  • Antioxidants are agents which inhibits oxidation and thus is used to prevent the deterioration of preparations by the oxidative process.
  • Such compounds include, by way of example and without limitation, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophophorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate and sodium metabisulfite and other materials known to one of ordinary skill in the art.
  • Binders are substances used to cause adhesion of powder particles in solid dosage formulations.
  • Such compounds include, by way of example and without limitation, acacia, alginic acid, carboxymethylcellulose sodium, poly(vinylpyrrolidone), compressible sugar (e.g., NuTab), ethylcellulose, hydroxypropyl methylcellulose, gelatin, liquid glucose, methylcellulose, povidone and pregelatinized starch and other materials known to one of ordinary skill in the art.
  • binders may also be included in the dosage forms.
  • exemplary binders include acacia, tragacanth, gelatin, starch, cellulose materials such as methyl cellulose, HPMC, HPC, HEC and sodium carboxy methyl cellulose, alginic acids and salts thereof, polyethylene glycol, guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers (PLURONICTM F68, PLURONICTM F127), collagen, albumin, gelatin, cellulosics in nonaqueous solvents, combinations thereof and others known to those skilled in the art.
  • binders include, for example, polypropylene glycol, poly oxy ethylene — polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide, combinations thereof and other materials known to one of ordinary skill in the art.
  • Buffering agents are compounds used to resist changes in pH upon dilution or addition of acid or alkali. Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and spdium citrate anhydrous and dihydrate and other materials known to one of ordinary skill in the art.
  • Sweetening agents are compounds used to impart sweetness to a preparation. Such compounds include, by way of example and without limitation, aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol, sucrose, and other materials known to one of ordinary skill in the art.
  • Diluents or fillers are inert substances used to create the desired bulk, flow properties, and compression characteristics in the preparation of solid dosage forms. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, lactose, dextrose, magnesium carbonate, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, calcium sulfate, sorbitol, and starch and other materials known to one of ordinary skill in the art.
  • Direct compression excipients are compounds used in compressed solid dosage forms. Such compounds include, by way of example and without limitation, dibasic calcium phosphate (e.g., Ditab) and other materials known to one of ordinary skill in the art.
  • Disintegrants are compounds used in solid dosage forms to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved.
  • Exemplary disintegrants include, by way of example and without limitation, starches such as com starch, potato starch, pre-gelatinized and modified starches thereof, sweeteners, clays such as bentonite, low substituted hydroxypropyl cellulose, microcrystalline cellulose (e.g., Avicel), methyl cellulose, carboxymethylcellulose calcium, sodium carboxymethylcellulose, alginic acid, sodium alginate, cellulose polyacrilin potassium (e.g., Amberlite), alginates, sodium starch glycolate, gums, agar, guar, locust bean, karaya, xanthan, pectin, tragacanth, agar, bentonite, and other materials known to one of ordinary skill in the art.
  • starches such as com starch, potato starch, pre-gelatinized and modified starches thereof, sweeteners,
  • Glidants are agents used in solid dosage formulations to promote flowability of the solid mass.
  • Such compounds include, by way of example and without limitation, colloidal silica, cornstarch, talc, calcium silicate, magnesium silicate, colloidal silicon, tribasic calcium phosphate, silicon hydrogel and other materials known to one of ordinary skill in the art.
  • Lubricants are substances used in solid dosage formulations to reduce friction during compression. Such compounds include, by way of example and without limitation, sodium oleate, sodium stearate, calcium stearate, zinc stearate, magnesium stearate, polyethylene glycol, talc, mineral oil, stearic acid, sodium benzoate, sodium acetate, sodium chloride, and other materials known to one of ordinary skill in the art.
  • Opaquants are compounds used to render a coating opaque. An opaquant may be used alone or in combination with a colorant. Such compounds include, by way of example and without limitation, titanium dioxide, talc and other materials known to one of ordinary skill in the art.
  • Polishing agents are compounds used to impart an attractive sheen to solid dosage forms. Such compounds include, by way of example and without limitation, carnauba wax, white wax and other materials known to one of ordinary skill in the art.
  • Colorants are compounds used to impart color to solid (e.g., tablets) pharmaceutical preparations. Such compounds include, by way of example and without limitation, FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No.
  • Flavorants are compounds used to impart a pleasant flavor and often odor to a pharmaceutical preparation.
  • Exemplary flavoring agents or flavorants include synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plants, leaves, flowers, fruits and so forth and combinations thereof.
  • cinnamon oil may also include cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leave oil, oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil.
  • Other useful flavors include vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and so forth.
  • Flavors which have been found to be particularly useful include commercially available orange, grape, cherry and bubble gum flavors and mixtures thereof. The amount of flavoring may depend on a number of factors, including the organoleptic effect desired. Flavors will be present in any amount as desired by those skilled in the art. Particularly contemplated flavors are the grape and cherry flavors and citrus flavors such as orange.
  • Complexing agents include for example EDTA disodium or its other salts and other agents known to one of ordinary skill in the art.
  • Exemplary fragrances include those generally accepted as FD&C grade.
  • Exemplary preservatives include materials that inhibit bacterial growth, such as Nipagin, Nipasol, alcohol, antimicrobial agents, benzoic acid, sodium benzoate, benzyl alcohol, sorbic acid, parabens, isopropyl alcohol and others known to one of ordinary skill in the art.
  • Solid dosage forms of the invention can also employ one or more surface active agents or cosolvents that improve wetting or disintegration of the core and/or layer of the solid dosage form.
  • Plasticizers can include, by way of example and without limitation, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols having aliphatic hydroxyls, ester-type plasticizers, glycol ethers, poly(propylene glycol), multi-block polymers, single block polymers, low molecular weight poly(ethylene glycol), citrate ester-type plasticizers, triacetin, propylene glycol and glycerin.
  • plasticizers can also include ethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol and other poly(ethylene glycol) compounds, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutylsebacate, acetyltributylcitrate, triethyl citrate, acetyl triethyl citrate, tributyl citrate and allyl glycolate.
  • plasticizers are commercially available from sources such as Aldrich or Sigma Chemical Co.
  • the PEG based plasticizers are available commercially or can be made by a variety of methods, such as disclosed in Poly(ethylene glycol) Chemistry: Biotechnical and Biomedical Applications (J.M. Harris, Ed.; Plenum Press, NY) the disclosure of which is hereby inco ⁇ orated by reference.
  • Solid dosage fomis of the invention can also include oils, for example, fixed oils, such as peanut oil, sesame oil, cottonseed oil, corn oil and olive oil; fatty acids, such as oleic acid, stearic acid and isostearic acid; and fatty acid esters, such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides.
  • fixed oils such as peanut oil, sesame oil, cottonseed oil, corn oil and olive oil
  • fatty acids such as oleic acid, stearic acid and isostearic acid
  • fatty acid esters such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides.
  • Alcohols such as ethanol, isopropanol, hexadecyl alcohol, glycerol and propylene glycol; with glycerol ketals, such as 2,2-dimethyl-l,3-dioxolane-4-rnethanol; with ethers, such as poly(ethyleneglycol) 450, with petroleum hydrocarbons, such as mineral oil and petrolatum; with water, or with mixtures thereof; with or without the addition of a pharmaceutically suitable surfactant, suspending agent or emulsifying agent.
  • alcohols such as ethanol, isopropanol, hexadecyl alcohol, glycerol and propylene glycol
  • glycerol ketals such as 2,2-dimethyl-l,3-dioxolane-4-rnethanol
  • ethers such as poly(ethyleneglycol) 450
  • petroleum hydrocarbons such as mineral oil and petrolatum
  • Soaps and synthetic detergents may be employed as surfactants and as vehicles for the solid pharmaceutical compositions.
  • Suitable soaps include fatty acid alkali metal, ammonium, and triethanolamine salts.
  • Suitable detergents include cationic detergents, for example, dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl and olefin sulfonates, alkyl, olefin, ether and monoglyceride sulfates, and sulfosuccinates; nonionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene)-&/ ⁇ ?c£-poly(oxy ⁇ ropylene) copolymers; and amphoteric detergents, for example, alkyl beta-aminopropionates and 2-alkylimidazoline quaternary
  • a water soluble coat or layer can be formed to surround a solid dosage form or a portion thereof.
  • the water soluble coat or layer can either be inert or drag-containing.
  • Such a coat or layer will generally comprise an inert and non-toxic material which is at least partially, and optionally substantially completely, soluble or erodible in an environment of use. Selection of suitable materials will depend upon the desired behavior of the dosage form.
  • a rapidly dissolving coat or layer will be soluble in the buccal cavity and/or upper GI tract, such as the stomach, duodenum, jejunum or upper small intestines. Exemplary materials are disclosed in U.S. Patents No. 4,576,604 to Guittard et al. and No.
  • Materials which are suitable for making the water soluble coat or layer include, by way of example and without limitation, water soluble polysaccharide gums such as carrageenan, fucoidan, gum ghatti, tragacanth, arabinogalactan, pectin, and xanthan; water-soluble salts of polysaccharide gums such as sodium alginate, sodium tragacanthin, and sodium gum ghattate; water-soluble hydroxyalkylcellulose wherein the alkyl member is straight or branched of 1 to 7 carbons such as hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; synthetic water-soluble cellulose-based lamina formers such as methyl cellulose and its hydroxyalkyl methylcellulose cellulose derivatives such as a member selected from the group consisting of hydroxyethyl methylcellulose, hydroxypropyl methylcellulose, and hydroxybutyl methylcellulose; croscarmellose sodium; other cellulose polymers such as water
  • lamina- forming materials that can be used for this pu ⁇ ose include poly(vinyl alcohol), poly(ethylene oxide), gelatin, glucose and saccharides.
  • the water soluble coating can comprise other pharmaceutical excipients that may or may not alter the way in which the water soluble coating behaves. The artisan of ordinary skill will recognize that the above-noted materials include film- forming polymers.
  • a water soluble coat or layer can also comprise hydroxypropyl methylcellulose, which is supplied by Dow under its Methocel E-15 trademark.
  • the materials can be prepared in solutions having different concentrations of polymer according to the desired solution viscosity. For example, a 2% W V aqueous solution of MethocelTM E-15 has a viscosity of about 13-18 cps at 20°C.
  • the compounds may be combined with skin penetration enhancers such as propylene glycol, polyethylene glycol, isopropanol, ethanol, oleic acid, N-methylpyrrolidone, or others known to those skilled in the art, which increase the permeability of the skin to the compounds, and permit the compounds to penetrate through the skin and into the bloodstream.
  • skin penetration enhancers such as propylene glycol, polyethylene glycol, isopropanol, ethanol, oleic acid, N-methylpyrrolidone, or others known to those skilled in the art, which increase the permeability of the skin to the compounds, and permit the compounds to penetrate through the skin and into the bloodstream.
  • the compound/enhancer compositions also may be combined additionally with a polymeric substance such as ethylcellulose, hydroxypropyl cellulose, ethylene/vinylacetate, or others known to those skilled in the art, to provide the composition in gel form, which can be dissolved in solvent such as methylene chloride, evaporated to the desired viscosity, and then applied to backing material to provide a patch.
  • a polymeric substance such as ethylcellulose, hydroxypropyl cellulose, ethylene/vinylacetate, or others known to those skilled in the art
  • the active ingredients may be combined with a sterile aqueous solution.
  • the solution may be isotonic with the blood of the recipient.
  • Such formulations may be prepared by dissolving one or more solid active ingredients in water containing physiologically compatible substances such as sodium chloride, glycine, or others known to those skilled in the art, and/or having a buffered pH compatible with physiological conditions to produce an aqueous solution, and/or rendering the solution sterile.
  • the formulations may be present in unit dose containers such as sealed ampoules or vials.
  • the active ingredients may be formulated with oils such as cottonseed, hydrogenated castor oil and mineral oil; short chain alcohols as chlorobutanol and benzyl alcohol; also including polyethylene glycols, polysorbates; polymers such as sucrose acetate isobutyrate, caboxymethocellusose and acrylates; buffers such as dihydrogen phosphate; salts such as sodium chloride and calcium phosphate; and other ingredients included but not exclusive to povidone, lactose monohydrate, magnesium stearate, myristyo-gamma-picolinium; and water.
  • oils such as cottonseed, hydrogenated castor oil and mineral oil
  • short chain alcohols as chlorobutanol and benzyl alcohol
  • polymers such as sucrose acetate isobutyrate, caboxymethocellusose and acrylates
  • buffers such as dihydrogen phosphate
  • salts such as sodium chloride and calcium phosphate
  • a solid dosage form of the invention can be coated with a finish coat as is commonly done in the art to provide the desired shine, color, taste or other aesthetic characteristics.
  • Materials suitable for preparing the finish coat are well known in the art and found in the disclosures of many of the references cited and inco ⁇ orated by reference herein.
  • Various other components can be added to the present formulation for optimization of a desired active agent release profile including, by way of example and without limitation, glycerylmonostearate, nylon, cellulose acetate butyrate, d,l-poly(lactic acid), 1,6-hexanediamine, diethylenetriamine, starches, derivatized starches, acetylated monoglycerides, gelatin coacervates, poly (styrene - maleic acid) copolymer, glycowax, castor wax, stearyl alcohol, glycerol palmitostearate, poly(ethylene), poly(vinyl acetate), poly(vinyl chloride), 1,3-butylene-glycoldimethacrylate, ethyleneglycol-dimethacrylate and methacrylate hydrogels.
  • glycerylmonostearate nylon, cellulose acetate butyrate, d,l-poly(lactic acid), 1,6-hexanediamine, diethylenetriamine
  • compositions for use in the methods of the present invention can be formulated in capsules, tablets, caplets, or pills.
  • Such capsules, tablets, caplets, or pills of the present inflammatory pain-alleviating compositions can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and penxiits the inner component to pass intact into the duodenum or to be delayed in release.
  • a variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the fomiulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • Controlled release or sustained-release dosage forms, as well as immediate release dosage forms are specifically contemplated. Controlled release or sustained release as well as immediate release compositions in liquid forms in which a therapeutic agent may be inco ⁇ orated for a ⁇ lministration orally or by injection are also contemplated.
  • the pharmaceutical compositions or dosage forms of this invention may be used in the form of a pharmaceutical preparation which contains one or more opioid antagonists in combination with one or more opioid agonists.
  • opioid antagonists undesirably bind significantly to certain pharmaceutical excipients.
  • Those pharmaceutical excipients generally cause an incomplete amount of the opioid antagonist to be released from a dosage form, within a particular time allotted for release.
  • opioid antagonists must be tested with pharmaceutical excipients, so as to ensure that the excipient does not bind the opioid antagonist to a significant degree.
  • Excipients for example, binders, disintegrants, glidants, lubricants, or acidifiers, as well as process conditions, such as pH, should be selected with this in mind.
  • compositions present herein for alleviating the symptoms or signs of arthritic conditions, chronic conditions associated with inflammation or chronic pain can be administered from about one time daily to about six times daily, two times daily to about four times daily, or one time daily to about two times daily.
  • Pain-alleviating compositions including inflammatory pain-alleviating compositions, presented herein preferably comprise at least one colloidal dispersion system, additive or preservative, diluent, binder, plasticizer, or slow release agent.
  • pu ⁇ oses compounds used in the art of pharmaceutical formulation generally serve a variety of functions or pu ⁇ oses. Thus, whether a compound named herein is mentioned only once or is used to define more than one term herein, its pu ⁇ ose or function should not be constraed as being limited solely to the named pu ⁇ ose(s) or function(s).
  • the present pain-alleviating compositions may be in admixture with an organic or inorganic carrier or excipient suitable for administration in enteral or parenteral applications, such as orally, topically, transdermally, by inhalation spray, rectally, by subcutaneous, intravenous, intramuscular, subcutaneous, intrathecal, epidural, perineural, intradermal, intraocular injection or infusion techniques.
  • such compositions are in the form of " a topical, intravenous, intrathecal, epidural, perineural, or oral formulation. More preferably, such compositions are in the form of an intrathecal, epidural or perineural formulation. Even more preferably, such compositions are in the form of an intravenous formulation. Most preferably, such compositions are in the form of an oral formulation.
  • the present invention is additionally advantageous because it can be used to enhance (e.g., increase) analgesic potency of the opioid agonists without substantially increasing the adverse side effects in humans associated with that dose of agonist.
  • the present methods and compositions may be employed in human subjects without significant increases in incidents of eye disorders, gastrointestinal disorders (such as upper abdominal pain, constipation, diarrhea, nausea, and vomiting), general disorders and conditions (such as lethargy), nervous system disorders (such as dizziness, headache, sedation, and sommolence), psychiatric disorders (such as euphoric mood), and skin and subcutaneous tissue disorders (such as pruritus).
  • gastrointestinal disorders such as upper abdominal pain, constipation, diarrhea, nausea, and vomiting
  • general disorders and conditions such as lethargy
  • nervous system disorders such as dizziness, headache, sedation, and sommolence
  • psychiatric disorders such as euphoric mood
  • skin and subcutaneous tissue disorders such as pruritus
  • a clinical study was designed as follows: (1) to evaluate the efficacy and safety of combinations of oxycodone (oxy) and naltrexone (ntx) administered twice daily and four times daily relative to oxycodone administered four times daily while maintaining the same total daily oxycodone dose, and (2) to evaluate the frequency and severity of opioid withdrawal in patients who received combinations of oxycodone and naltrexone compared to those patients who received oxycodone.
  • a daily diary was to be utilized to record overall pain intensity (PI) and other signs and symptoms.
  • the patient was enrolled in the study if: (1) the mean value of the diary PI over the last 2 days of the 4- to 7-day baseline period was > 5; (2) the confirmatory PI obtained at the baseline clinic visit was also > 5; and, (3) the patient met all inclusion exclusion criteria.
  • Baseline functional assessments were conducted with the SF-12 Health Survey as shown in Table 1 and the Western Ontario and MacMaster Universities Osteoarthritis Index (WOMAC) as shown in Table 2 below before the initiation of study medication. Table 1 The SF-12v2TM Health Survey
  • This table shows the 10 items of SOWS and the format in which it is administered.
  • the Study Population was three hundred sixty-two (360) patients with moderate to severe chronic pain due to osteoarthritis of the hip or knee. According to the study design described above, there were to be about 100 patients each in the oxycodone and naltrexone BID, oxycodone and naltrexone QID and oxycodone alone treatment groups; and about 50 patients in the placebo group.
  • Inclusion criteria were as follows: (1) Males and females who were > 18 and ⁇ 70 years of age; (2) Females who were postmenopausal, physically incapable of childbearing, or practicing an acceptable method of birth control.
  • Acceptable methods of birth control included surgical sterilization, hormonal contraceptives, or double-barrier methods (condom or diaphragm with a spermicidal agent or IUD). If practicing an acceptable method of birth control, a negative urine pregnancy test result was obtained at the Screening Nisit; (3) Patient was ambulatory; (4) Patient had moderate to severe pain in one or more hip or knee joint(s) caused by osteoarthritis for at least three months prior to the Screening Nisit; (5) Patient had moderate to severe pain in the hip or knee joint(s) while taking one or more oral analgesic medication(s) (e.g., NSAIDs, COX-2 inhibitors, tramadol, opioid) in the past one month prior to the Screening Visit; (6) Patient had a pain intensity score of > 5 on an 11 -point numerical scale at the Screening Visit; (7) Patient had a mean daily diary overall pain intensity (taken immediately before their bedtime dose of acetaminophen) of > 5 on an 11 -point numerical scale during the
  • Exclusion criteria for subjects were as follows: (1) Patient had received a daily opioid dose equivalent (if applicable) of oxycodone > 20 mg for two or more days within four weeks prior to the Screening Visit (as calculated by the Drug Conversion Calculator Version 2.0, American Pain Study); (2) Patient had received an opioid within 72 hours of the Screening Visit; (3) Patient weighed more than 300 lbs or less than 100 lbs; (4) Patient had major surgery within three months prior to the Screening Visit or had surgery planned for this joint during the proposed study period; (5) Patient had received oral or parenteral corticosteroid therapy within one month prior to the Screening Visit; (6) Patient had received an intraarticular injection of hyaluronic acid within nine months prior to the Screening Visit; (7) Patient had received any epidural or intrathecal infusion of any analgesic medication(s) within one month prior to the Screening Visit; (8) Patient was pregnant or breast-feeding; (9) Patient had a history of severe hepatic or renal impairment; (10) Patient had acute hepatitis; (1
  • analgesic medication other than acetaminophen - up to 5 caplets per day
  • Pain Control was also assessed weekly at clinic visits. The patient was prompted with the question, "During the past week, how would you describe your pain control during the course of each day?" Responses were selected from: Pain was controlled for (1) a few hours or less each day; (2) several hours each day; (3) most of each day; and (4) throughout each day.
  • Safety procedures included vital signs (blood pressure, respiratory rate, heart rate and temperature), physical examinations, EKGs, clinical laboratory tests, adverse events, opioid toxicity assessments and the assessment of opiate withdrawal symptoms using the SOWS (see Table 6).
  • the opioid toxicity assessment included: (A) CNS review by assessing for (1) confusion, altered mental state, (2) excessive drowsiness, lethargy, stupor, (3) slurred speech (new onset), (4) respiratory, (5) • hypoventilation, shortness of breath, apnea, (6) hypoxia, hypercarbia; and (b) cardiac review by assessing for bradycardia, hypotension, and shock. If patients experienced any of these or other symptoms that, in the principal investigator's opinion, would pose a significant risk if additional opioid doses were administered, doses were not escalated on Week 2, Day 1 or Week 3, Day 1.
  • pre-enrollment screening was perfonned.
  • the following assessments were conducted at Visit 1, four to seven days prior to enrollment in the study: (1) written informed consent, (2) clinic PI, (3) review inclusion and exclusion criteria, (4) detailed medical history including concomitant medications taken one month prior to the screening visit, (5) complete physical examination including height, weight and vital signs, (6) EKG (QTc interval only), (7) blood samples for clinical laboratory tests (hematology and chemistry), (8) urine sample for clinical laboratory tests, (drug screening and urinalysis), (9) urine pregnancy test for all women of childbearing potential, and (10) dispense acetaminophen, take-home diary and provide an appointment card for the next visit.
  • the diary issued at Visit 1 was to be used by the patient to record the following information at bedtime immediately before the patient's dose of acetaminophen was taken: (a) overall PI in the past 24 hours, (b) signs and symptoms, and (c) date/time of each acetaminophen dose.
  • the second visit was on the first day of the first treatment week of the study.
  • the patients returned to the study center four to seven days after the Screening Visit for completion of the pre-dose assessments.
  • This visit included (1) reviewing the take-home diary from the past four to seven days; (2) collecting the bottle of acetaminophen and performing accountability; (3) a baseline clinic PI rating, (4) reviewing inclusion and exclusion criteria.
  • This assessment also included verifying that (a) the mean daily overall pain intensity score collected in the diary over the last two days of the 4- to 7-day washout period was > 5 (on a scale of 0 to 10) while off all analgesic medications (except acetaminophen as directed); (b) the clinic PI at this visit measured > 5 (on a scale of 0 to 10); and (c) checking that the clinical laboratory tests results from the screening visit were without significant clinical abnonnalities, that the urine pregnancy test was negative (if required), and that the urine drug screen was negative.
  • the study medication kit was dispensed for Week 1 (Study Days 1-8). Patients were instructed to take up to three doses of study medication on this day (noon, afternoon and at bedtime). In addition, patients were instructed to take their Day 8 'waking' dose from this medication kit. The patients received their take-home daily diaries and were provided with an appointment card for the next visit. The study nurse thoroughly reviewed each section of the diary with the patient. The daily diary issued at Visit 2 was used to record the following information at Bedtime immediately prior to dosing: (1) overall PI in the past 24 hours; (2) Date and time of each dose of study medication taken; and (3) adverse events. [216] Patients were contacted by telephone on the evenings of Days 3 and 4 of Treatment Week 1.
  • the study center contacted patients before noon once daily (for four days after the last dose of study medication) to monitor for symptoms of opioid withdrawal. On each telephone call, the study center verified that the SOWS have been completed each day (in the morning) by the patients. In addition, there was a check for adverse events and concomitant medications. If necessary, a clinic visit was required for those patients with clinically significant withdrawal symptoms. [227] Patients returned to the study center approximately one week ( ⁇ two days) after the last dose of study medication for a post-treatment follow-up visit. At this visit, the following assessments were completed: (1) review take-home diary; and (2) record new/changed adverse events and concomitant medications.
  • the primary analysis population for both efficacy and safety included all patients who took study medication. In the event that a patient was randomized incorrectly or was otherwise administered the incorrect study drug, the patient was to be analyzed according to the study drug actually received.
  • the daily pain intensity ratings were summarized as follows. For each week, the in intensity recorded on the last two full days of dosing within the week, restricted to Day 5 or later, was averaged. If only a single observation was available, it was used; otherwise, the endpoint was not defined. The pain intensity averages were represented as both (1) a change from baseline and (2) a percent change from baseline. The baseline value was defined as the average pain intensity over the last two values recorded during the baseline period; if necessary, a single value was used. [233] The global assessment, quality of analgesia, and pain control, recorded at the end of each week, were summarized in terms of category proportions.
  • the primary efficacy endpoint was the percent change from baseline in pain intensity at Week 3. Percent change in pain intensity was analyzed using ANOVA methods.
  • the ANOVA model included factors for treatment, sex, and their interaction. Additional covariates could be added to the model for exploratory purposes. Pairwise treatment group comparisons were made using contrasts within the ANOVA framework. Testing employed Type III sums of squares. If the assumptions of the parametric tests were not valid, non- parametric tests were used.
  • Adverse events reported were mapped to preferred terms and organ systems using the MedDRA mapping system. Adverse events were associated with weeks according to their onset date. The number and percentage of patients reporting each event were summarized by treatment group and week.
  • Results were obtained using nQuery Advisor , version 4.0 (Statistical Solutions Ltd., Boston, MA). ⁇ • . ' • • '
  • Tables 8A, 8B, and 8C for males and 8E, 8F and 8G for females show averages for actual values for Pain Intensity at Weeks 1, 2 and 3, respectively.
  • Tables 8D and 8H show baseline values for males and females, respectively.
  • Tables 9A, 9B and 9C show the percent change from baseline PI scores at Weeks 1, 2 and 3, respectively.
  • a quality of analgesia assessment at Week 3 of very good or excellent was reported by 12.0% of patients treated with placebo, 19.6% of patients treated with oxycodone alone QID, 10.6% of patients with oxycodone plus naltrexone QID, and 33.3% of patients treated with oxycodone plus naltrexone BID.
  • Tables 11 A, 1 IB and 1 IC also show thep value vs. placebo calculated for the scores from the global assessment for Weeks 1, 2 and 3, respectively, which were determined using the Cochran-Mantel-Haenszel row mean scores (CMH-RMS) test, using equally spaced scores.
  • CMH-RMS Cochran-Mantel-Haenszel row mean scores
  • Table 1 IC generally show a population shift from patient responses of poor and fair toward patient responses of very good and excellent when comparing the placebo group to the oxycodone alone QID, oxycodone plus naltrexone QID and oxycodone plus naltrexone BID treatment groups. Larger percentages of patients in the oxycodone plus naltrexone BID treatment group gave responses of very good or excellent.
  • 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 C5 ⁇ ⁇
  • Tables 12 A, 12B and 12C also show the p value vs. placebo calculated for the scores from Pain Control, which were determined using the Cochran-Mantel-Haenszel row mean scores (CMH-RMS) test, using equally spaced scores.
  • CH-RMS Cochran-Mantel-Haenszel row mean scores
  • 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.
  • Another efficacy endpoint for this study was a functional assessment using WOMAC, including its three subscales for pain, stiffness and physical function.
  • the actual values from the WOMAC pain subscale are shown in Tables 13 A, 13B and 13C for Weeks 1, 2 and 3, respectively and Table 13D shows the baseline values. Greater improvements (% change from baseline to Week 3) were observed with BID administration of oxycodone plus naltrexone in all categories (pain, stiffness, or physical function).
  • Oxycodone plus naltrexone BID was statistically significantly better than placebo at Weeks 2 and 3 as measured by the WOMAC pain subscale, stiffness subscale, physical function subscale and total score, as shown below in Tables 13A, 13B and 13C (pain), 14A, 14B and 14C (stiffness), 15A, 15B and 15C (physical function) and 16A, 16B and 16C (total score).
  • the A, B and C tables show the values at Weeks 1, 2 and 3, respectively and the D tables show the baseline values.
  • S AEs Serious adverse events
  • the Short Opioid Withdrawal Scale (SOWS) (see Table 6 above), originally used for collecting withdrawal data from heroin addicts, was used to assess opioid withdrawal in this study. Although there were statistically significant differences between treatment groups, the differences were considered clinically insignificant because both the mean SOWS changes and the differences of their changes were of small magnitude. The lack of clinically significant opioid withdrawal in this study is attributable to the relatively low opioid doses and short treatment duration. Opioid withdrawal was not reported as an adverse event in any of the treatment groups.
  • Oxycodone plus naltrexone BID was shown to be a safe and effective treatment for patients with chronic pain and with osteoarthritis of the hip or knee.
  • Oxycodone plus naltrexone BID provided statistically and clinically significant reductions in pain intensity compared to oxycodone alone QID when the same total daily dose of oxycodone was administered.
  • the overall incidence of opioid-related adverse events was comparable in the oxycodone plus naltrexone and oxycodone alone treatment groups and no clinically meaningful effects on vital signs, laboratory safety tests or QTc interval changes were noted in the oxycodone plus naltrexone or oxycodone alone treatment groups.
  • Oxycodone plus naltrexone BID provided better daily pain control to that of oxycodone alone QID.
  • Oxycodone plus naltrexone BID showed greater improvements in all categories of the WOMAC Osteoartliritis Index (pain, stiffness and physical function) when compared to the other active treatment groups.
  • a multicenter, randomized, double-blind, active- and placebo-controlled, clinical study was designed and is conducted. The study evaluates the efficacy and safety of an oral formulation of oxycodone and naltrexone relative to oxycodone and to naltrexone over a 12- week fixed-dose period following one week of titration (instead of a three week period).
  • a total of 750 patients (instead of 360 patents) with chronic pain due to osteoarthritis of the hip or knee are enrolled into six (instead of four) treatment groups: three groups for combinations of oxycodone and naltrexone, a group for oxycodone alone, a group for naltrexone alone and a group for placebo.
  • the Study Population is seven hundred fifty (750) patients with moderate to severe clironic pain due to osteoarthritis of the hip or knee. According to the study design described above, there are 150 patients each in the oxycodone and naltrexone BID, oxycodone and naltrexone QID and oxycodone alone treatment groups; and 75 patients each in the naltrexone and placebo groups.
  • the inclusion criteria are essentially the same as described above in Part A, with the following exceptions: Patient agrees to refrain from taking any pain medications other than study drug during the 13- week treatment period, rather than the shorter treatment period of the clinical study of Part A. (Aspirin [up to 325 mg/day] is permitted for cardiovascular prophylaxis if at a stable dose one month prior to the Screening Visit.); and Patient is able to ambulate for a specified distance (at least 100 meters). [262] The exclusion criteria are essentially the same as described above in Part A, with the exceptions listed below.
  • Additional exclusion criteria are as follows: (a) Patient has a positive urine drug screen at the Baseline/Titration Nisit NOT caused by any therapeutic medication permitted during the study; (b) Patient has pain in the hip(s) or knee(s) caused by conditions other than osteoarthritis, e.g., malignancy, gout, inflammatory disease such as rheumatoid arthritis, trauma, fibromyalgia, bony fracture, or infection; (c) Patient has a history of cardiac disease (such as coronary artery disease, cardiomyopathy, congestive heart disease, valvular disease, arrythmia, etc.), angina, myocardiac infarct (MI), cerebral aneurysm, cerebral vascular accident (CNA), transient ischemic event (TIA), inadequately controlled hypertension, or health condition(s) which poses significant health risk in the event of opioid withdrawal; (d) Patient has started or stopped physical therapy, transcutaneous electrical nerve stimulation, chiropractic, osteopathic, acupuncture, or other
  • acetaminophen is dispensed as described in Part A.
  • the investigational drug supplies are in tablet dosage forms containing oxycodone HCl and naltrexone HCl, oxycodone HCl, naltrexone or placebo. All of the tablet dosage forms are indistinguishable from one another to facilitate blinding. Tablets are arranged on each blister card by Study Day and contain four doses per day. Each blister card also contains three days of extra study drug to allow for flexibility in planning return clinic visits. The extra study drug must remain intact within its original packaging so that it may be returned during each clinic visit. The investigational drug supplies are dispensed in these kits.
  • Safety procedures include those described in Part A.
  • the opioid toxicity assessment includes: (A) CNS review by assessing for (1) confusion, altered mental state, (2) excessive drowsiness, lethargy, stupor, (3) slurred speech (new onset), (B) respiratory review by assessing for (1) hypoventilation, shortness of breath, apnea, (2) decreased respiratory rate ( ⁇ 8) or cyanosis; and (3) cardiac review by assessing for heart rate ⁇ 60, hypotension. If patients must be terminated from the study, the Early Drug Termination assessments and opioid withdrawal monitoring (as needed) are performed as discussed below.
  • pre-enrollment screening is performed as described in Part A.
  • the second visit is on the first day of the first titration period of the study.
  • the patients returned to the study center four to seven days after the Screening Visit for completion of the pre-dose assessments.
  • This visit included (1) obtaining a urine sample for drag screening using a rapid drug screen kit (BioChek /CupTM Drug Screen). If positive for any drugs not caused by any therapeutic medication permitted during the study, no further assessments are made. Patient cannot continue in the study; (2) reviewing the take-home diary from the past four to seven days; (3) collect bottle of acetaminophen and perform accountability, (4) baseline clinic PI rating; and (5) reviewing inclusion and exclusion criteria.
  • This assessment also includes verifying that (a) the mean daily overall pain intensity score collected in the diary over the last two days of the 4- to 7-day washout period is > 5 (on a scale of 0 to 10) while off all analgesic medications (except acetaminophen as directed); (b) the clinic PI at this visit measures > 5 (on a scale of 0 to 10); and (c) checking that the clinical laboratory tests results from the screening visit are without significant clinical abnormalities, and that the urine pregnancy test is negative (if required).
  • the study medication kit is dispensed for the titration period.
  • the patients received their take-home daily diaries and are provided with an appointment card for the next visit.
  • the study nurse thoroughly reviewed each section of the diary with the patient.
  • the daily diary issued at Visit 2 is used to record the following information at bedtime immediately prior to dosing: (1) overall PI in the past 24 hours; and (2) adverse events.
  • a patient chooses to discontinue study drag early, the investigator must request that the patient return to the clinic within 24 hours of stopping the study medication and complete the end of study assessments described above. For patients who have been on study medication for > 4 weeks, Day 1 of the opioid withdrawal monitoring period begins 24 hours after the last dose of study medication. The investigator can request that the patient remain in the study for the post-treatment follow-up visit. Study drug assigned to patients who discontinue early may not be reassigned.
  • the primary analysis population is the intent-to-treat (ITT) population.
  • ITT intent-to-treat
  • the ITT population will consist of all patients who take study medication and are used for both efficacy and safety analyses. In the event that a patient is randomized incorrectly or is administered the incorrect study medication, the patient is analyzed according to the study drug actually received. Additional analysis populations may be defined as appropriate based on the actual study experience.
  • Demographic variables and patient characteristics are summarized descriptively by treatment group and overall. Demographic variables will include age, weight, height, gender, and race/ethnicity. Baseline characteristics includes the PI score recorded in the clinic and baseline values of efficacy variables. Baseline and post-baseline patient characteristics includes study drug administration and prior and concomitant medications.
  • Daily diary PI score The daily PI assessments are analyzed as weekly values as follows. For each post-baseline week, the PI recorded during the last two days of dosing within the week are averaged.
  • Baseline PI is defined as the average PI recorded during the two days immediately prior to the Baseline/Titration visit; (2) Quality of analgesia — assessed and analyzed by clinic visit (weekly for the first five weeks and biweekly thereafter); (3) Pain control — assessed and analyzed by clinic visit (weekly for the first five weeks and biweekly thereafter); (4) Global assessment of study medication — assessed and analyzed by clinic visit (weekly for the first five weeks and biweekly thereafter); (5) SF-12 Health Survey — assessed and analyzed monthly; scored as described in the documentation (e.g., Ware et al., 1998); and (6) WOMAC Osteoarthritis Index — assessed and analyzed monthly; calculated per the WOMAC User Guide.
  • Missing efficacy data is imputed using the last-observation-carried-forward (LOCF) approach. If the number of patients per center is small, centers may be pooled for analysis, or omitted from statistical models. Unless otherwise indicated, all testing of statistical hypotheses is two-sided, and a difference resulting in a j ⁇ -value of less than or equal to 0.05 is considered statistically significant.
  • LOCF last-observation-carried-forward
  • the primary efficacy endpoint is the percent change from baseline to Visit 11 (Week 12 or early drag termination) in average daily PI.
  • An analysis of covariance (ANCOVA) model is employed, as described below.
  • the pairwise treatment comparison that is of primary interest is treatment group A ([OXY 20 mg + NTX 0.001 mg] during the fixed-dose period) vs. treatment group D (OXY lO mg QID during the fixed-dose period).
  • WOMAC Osteoartliritis Index is analyzed in terms of the values themselves as well as in terms of change and percent change from baseline. These variables are summarized descriptively by treatment group and by sex. Treatments are compared globally and in pairwise fashion at each time point using an analysis of covariance (ANCOVA) model that includes treatment, center, and sex as factors and baseline value as a covariate. Potential interactions are assessed by also fitting a model with the same main effects and with the treatment by center, treatment by sex, and treatment by baseline interaction terms. In addition, pairwise t-tests are used to compare each post-baseline time point to each prior time point, within treatment group, overall and by sex.
  • ANCOVA analysis of covariance
  • Sensitivity analyses are carried out to determine the extent to which the statistical analysis results are influenced by the choice to impute missing observations using LOCF.
  • the primary analysis is repeated using one or more alternative imputation methods (e.g., imputing data following withdrawal depending on the reason for withdrawal) and using an appropriate longitudinal analysis technique such as repeated measures mixed-effects analysis of variance.
  • an "observed data” analysis is conducted on selected endpoints using the same analysis methods described previously.
  • Adverse events are reported and examined as described in Part A. Change from baseline is summarized descriptively for vital signs and QTc interval. Laboratory data is summarized descriptively on the original scale, change from baseline, and in terms of the normal range.
  • EXAMPLE 2 A clinical study was conducted as described in Example 1 wherein safety and analgesic effects of oxycodone or a combination of oxycodone and naltrexone were measured in patients with chronic pain as described in Example 1. Plasma concentrations of the administered drugs and their major metabolites were measured to determine: (1) oxycodone absorption from the combination drug of oxycodone and naltrexone; (2) dose proportionality of plasma concentrations of oxycodone and oxymorphone from the combination drug of oxycodone and naltrexone; (3) achievement of steady state of plasma concentrations of oxycodone, oxymorphone and 6 ⁇ -naltrexol from the combination drag of oxycodone and naltrexone; and (4) consistency of the half-life and clearance of oxycodone over the course of the study. The relationships between clinical outcomes and the plasma concentrations of oxycodone, oxymorphone, and 6 ⁇ -naltrexol were plotted for each treatment as
  • linear equation coefficients were obtained by averaging patient-specific slopes and intercepts obtained by within-patient least squares regression. This was done to account for the correlation among the repeated measurements due to the patient's contributing data at each dose level.
  • the resulting slopes among treatment groups were compared by one-way analysis of variance (ANOVA), and a one- sample t-test assessed the common slope's difference from zero.
  • a measure of deviation from linearity was constructed as the difference between the concentration at the middle dose versus the average of the concentrations at the lower and higher doses. Due to equal spacing of doses, this measure has expectation zero under the hypothesis of linearity.
  • ANOVA and t- tests were used to assess linearity.
  • box-and-whisker plots were used to summarize the distribution of variables. Those figures depict either the minimum value in the data or selected outliers at the lower end, the quartile (25th percentile), the median, the upper quartile (75th percentile) and the maximum or selected outliers at the upper end.
  • the total daily dose of oxycodone was equal in active treatment arms; i.e., the oxycodone dose in individual doses of the combination drag of oxycodone and naltrexone QID or oxycodone QID was half that of the combination drug of oxycodone and naltrexone BID.
  • the linear equation coefficients were obtained by averaging patient-specific slopes and intercepts obtained by within-patient least squares regression.
  • Figure 3 shows the box-and-whisker plots of the plasma concentrations for oxycodone for each treatment group.
  • Figure 4 shows the box-and-whisker plots of the transformed plasma concentrations for oxycodone for each treatment group.
  • the median plasma concentrations of oxycodone are not different following the final dose for each treatment group (* indicates outlying value).
  • the median log-transformed plasma concentrations of oxycodone are not different following the final dose for each treatment group (* indicates outlying value).
  • Figure 5 shows the box-and-whisker plots of the transformed plasma concentrations of oxymorphone for each treatment group.
  • the median log-transformed plasma concentrations of oxymorphone are not different following the final dose for each treatment arm (* indicates outlying value).
  • Figure 6 the plasma concentrations of oxycodone and oxymorphone normalized by dose remained constant throughout the study, irrespective of treatment group, suggesting that steady state is achieved and maintained.
  • Figure 7 the plasma concentrations of 6 ⁇ -naltrexol, the major metabolite of naltrexone and a marker for its concentration, remained constant throughout the study (sampled at the end of each treatment week).
  • naltrexone maintained constant concentrations of 6 ⁇ -naltrexol, the major metabolite of naltrexone, suggests that naltrexone reached steady state by the end of Week 1 regardless of a 2- fold difference in dose and dosing frequency between treatments.
  • Plasma concentrations of oxycodone and its metabolites, as well as the major metabolite of naltrexone (6 ⁇ -naltrexol) showed stable pharmacokinetic parameters indicating that the dosage regimens for the combination drug of oxycodone and naltrexone are predictable and easy to manage.
  • Comparisons of the BID and QID dosing regimens for the combination drag of oxycodone and naltrexone showed good correlation between 6 ⁇ -naltrexol concentration and statistically significant reduction in pain intensity and the percentage change in pain intensity.
  • Plasma concentrations of oxycodone and oxymorphone did not correlate with greater pain relief and the lowest dose of naltrexone (from the administration of the combination drug of oxycodone and naltrexone BID) utilized in this study resulting in the lowest plasma concentrations of 6 ⁇ -naltrexol, as a measure of naltrexone plasma concentrations, corresponded to greater pain relief.
  • PK/PD pharmacokinetic/pharmacodynamic
  • Example 2 As described in Example 2, the oxycodone and oxymorphone plasma concentration data showed a skewed distribution commonly seen in pharmacokinetic (PK) data. To achieve symmetry, modified log transformations were used as described in Example 2. As noted in Example 2, 6 ⁇ -naltrexol plasma concentrations did not require transformation to achieve an approximately Gaussian distribution. Table 21 shows the correspondence between the transformed and original scales (where "a" indicates beyond range of observed data).
  • Pharrnacodynamic outcome measures as described in Example 2 and Figures 8 - 10 were paired with the appropriate analyte plasma concentrations for PK/PD analyses.
  • the plasma concentrations of oxycodone, oxymorphone, naltrexone and 6 ⁇ naltrexol were measured. It has been observed that plasma concentrations of naltrexone are about one-tenth the plasma concentrations of 6 ⁇ -naltrexol in the same plasma samples. Accordingly, 6 ⁇ -naltrexol plasma concentrations are useful as indicators of naltrexone plasma concentrations and to identify preferred plasma concentrations of naltrexone.
  • PK/PD analytes were oxycodone and oxymorphone plasma concentrations individually paired with: pain intensity at final visit; pain intensity percent change from baseline at final visit; patient's global assessment at final visit; quality of analgesia at final visit; WOMAC-pain at final visit; WOMAC-pain percent change from baseline at final visit; WOMAC-stiffhess at final visit; WOMAC-stiffness percent change from baseline at final visit; WOMAC-physical function at final visit; WOMAC-physical function percent change from baseline at final visit; WOMAC-total score at final visit; and WOMAC-total score percent change from baseline at final visit.
  • the main PK assessment used linear regression analysis to fit the time-concentration profiles.
  • One-way analysis of variance was used to compare active treatment arms with respect to average oxycodone and oxymorphone plasma concentration (ignoring time of blood draw). Pearson correlation coefficients and associated p- values were used to describe the relationship between plasma concentration versus the outcome measures.
  • Regression analyses combined with F-tests on the extra sums of squares were used to assess whether the time-concentration profiles and correlations differed among the three active treatment arms. P-values were computed and reported without adjustment for multiple testing.
  • statistical analyses except extra sum of squares analyses were perfonned using MI ⁇ ITAB ® , release 14.1.
  • the extra sum of squares analyses were calculated using Microsoft Excel, with Minitab sums of squares as input.
  • the first row of data displays correlation coefficients, and the second row displays corresponding p-values.
  • Figures 11 and 12 illustrate this plasma concentration-effect relationship.
  • Figure 11 plots ' the percent change in pain intensity reported by the subjects in Table 25 (y-axis) vs. 6 ⁇ -naltrexol plasma concentrations measured for those subjects (x-axis).
  • Figure 11 includes data from subjects receiving the BID dosing regimen of the combination drug and subjects receiving the QID dosing regimen of the combination drug.
  • Figure 12 plots the percent change in pain intensity reported by the subjects receiving the BID dosing regimen of the combination drug vs. 6 ⁇ -naltrexol plasma concentrations measured for those subjects.
  • E [Emaxl (Cp nl )/EC51 ttl + Cp nI ] + [Emax2 (Cp n2 )/EC52 n2 + Cp" 2 ]
  • Emax values represent maximum effect for a given drug
  • EC51 and EC52 represent the potencies, for the drag notated as either 1 or 2, respectively (in other words, EC51 is not the concentration having 51% of the maximal effect, but rather EC51 is the concentration having a particular potency (e.g. 50% of the maximal effect for Effect No.
  • the respective values for C are the concentrations of drugs notated as 1 or 2, and the values of m and ⁇ 2 that correspond to the sigmoidicity factors that are associated with particular EC values.
  • "+" is used to indicate absolute values; sometimes it is shown as a "-" which reflects a negative second term.
  • the Emax composite model is a recognized composite model for PK/PD data analysis set forth, for example, in Gabrielsson et al, PHARMACOKINETIC/PHARMACODYNAMIC DATA ANALYSIS: CONCEPTS AND APPLICATIONS, pp. 191-193 and 801-808 (2000), and the computer command files provided with the reference and described, including with examples of the computer printouts on pages 801-808, all of which is inco ⁇ orated by reference herein.
  • opioid antagonists such as naltrexone for enhancing the potency of opioid agonists such as oxycodone, as described herein. From the plasma concentration-effect data obtained in this Example, it is contemplated that the opioid antagonist, at lower plasma concentrations, is impacting the total effect (percent change in pain intensity), primarily as described by the terms of the equation denoted with a 2.
  • the plasma concentration-effect data were fit to the Emax composite model using the software program WinNonlin® (commercially available from Pharsight Corporation of Mountain View, California) and the command files developed by Gabrielsson et al.
  • the plasma concentration-effect data represented as circles in Figure 11 were evaluated mathematically and the plasma concentration- effect curve shown in Fig. 11 was determined by the program and command files.
  • the program and command files were used to determine the plasma concentration-effect curve shown in Figure 12 based on the data represented as circles in Figure 12.
  • the computer output (printout) of this process included EC51 and EC52 parameters, as well as parameters reflecting statistical evaluation of the data, such as coefficient of variation (CN%).
  • EC51 and EC52 parameters included EC51 and EC52 parameters, as well as parameters reflecting statistical evaluation of the data, such as coefficient of variation (CN%).
  • a variety of values, for example EC20 and EC90 may also be determined using the output from the WinNonlin® program and Gabrielsson et al. command files (or similar programs and command files).
  • Other values, for example ECO and EC 100 and all values in between, also may be determined graphically and/or using the values of Nl and N2 that correspond to the sigmoidicity factors.
  • Table 26 shows parameters based on the curve shown in Figure 11. These parameters are based on the data for 6 ⁇ -naltrexol plasma concentrations and reduction in pain from baseline pain intensity to final pain intensity from all subjects for whom plasma concentration data was obtained as described herein. These parameters are based on data from subjects receiving the BID dosing regimens and subjects receiving the QID dosing regimen. Estimate refers to the value estimated by the WinNonlin® program and command file for relating plasma concentrations to the pharmacodynamic effects such as percent reduction in pain intensity. Convergence of the model was easily achieved and the power of the condition number was acceptable. Table 26
  • Table 27 shows parameters based on the curve shown in Figure 12. These parameters are based on the data (6 ⁇ -naltrexol plasma concentrations and percent reduction in pain intensity) for subjects receiving BID dosing regimens. Convergence of the model was easily achieved and the power of the condition number was acceptable. Table 27 Parameters based on BID data
  • the BID dosing regimen of the combination drug comprising naltrexone and oxycodone resulted in statistically significant decreases in pain intensity.
  • the Einax composite model provided the value of a EC52 plasma concentration of 6 ⁇ -naltrexol based on that BID dosing regimen.
  • Substantially the same EC52 result was obtained from the analysis of the total data set (comprising data from both the BID and QID dosing regimens).
  • the fact that substantially the same EC52 result was obtained from the different data sets supports the strength of the Emax composite model for analysis of the data. It also supports the use of the Emax composite model in order to select desirable doses of naltrexone (or another opioid antagonist) in combination with oxycodone.
  • Tables 26 and 27 illustrate the use of the total set of clinical data and the subset associated with positive clinical results in the same Emax composite model to provide two sets of parameters. Either or both of the two sets of parameters can be used to identify plasma concentrations having a probability of attaining a desired reduction of pain intensity or other efficacy outcome (e.g., pharmacodynamic outcome) as described herein. From the plasma concentration-effect data and the Emax composite model, one can better assess what plasma concentrations of 6 ⁇ -naltrexol provide desired reduction in pain intensity and, more generally, better pain treatment.
  • dosage forms for oral administration to a human subject comprise a dose amount of opioid antagonist that is based on a selected plasma concentration.
  • opioid antagonist e.g., as shown in Table 25
  • naltrexone and/or 6 ⁇ - naltrexol may be used to titrate a subject to the appropriate dose for that subject thus providing a convenient means for individualized dosing.
  • the Emax composite model can facilitate dose titration for a human subject.
  • Dose titration refers to the process of employing different doses (usually escalating doses) in a subject until a dose effective to achieve a desired clinical outcome is found.
  • Dose titration for the administration of an opioid antagonist and/or an opioid agonist according to the present invention may be facilitated by using plasma concentrations of 6 ⁇ -naltrexol, naltrexone, or another marker of opioid antagonist.
  • Dose titration may also be facilitated by using plasma concentrations of oxycodone, oxymorphone, or another marker of opioid agonist may be used alone or in combination with a marker of opioid antagonist for dose titration.
  • the subject's plasma concentration of 6 ⁇ -naltrexol, naltrexone or another marker for opioid antagonist is analyzed, and one or more clinical outcomes (such as reduction in pain intensity) for the subject are analyzed. If a desired clinical outcome is not achieved (for example, if pain intensity is not reduced to a desired level), the administration of opioid antagonist and/or opioid agonist to the subject is adjusted.
  • the composite model can be used to facilitate adjusting, or facilitate the decision to adjust, the administration of (a) the opioid antagonist or (b) the opioid agonist or (c) both.
  • the plasma concentration of 6 ⁇ -naltrexol is analyzed. If the 6 ⁇ -naltrexol plasma concentration is not at a desired level, then administration of the opioid antagonist to the subject is adjusted. The administration of the opioid antagonist may be adjusted by adjusting the dose amount and/or dosing regimen. However, if the 6 ⁇ -naltrexol plasma concentration is already at a desired level, yet the clinical outcome is not at a desired level, then the administration of the opioid agonist to the subject is adjusted. The administration of the opioid agonist may be adjusted by adjusting the dose amount and/or dosing regimen.
  • the plasma concentration of 6 ⁇ -naltrexol is analyzed. If the 6 ⁇ - naltrexol plasma concentration is below a desired level, then administration of the opioid antagonist to the subject is adjusted so that more opioid antagonist is administered to the subject. If the 6 ⁇ -naltrexol plasma concentration is above a desired level, then administration of the opioid antagonist to the subject is adjusted so that less opioid antagonist is administered to the subject.
  • the Emax composite model may be used to identify desired levels of the plasma concentration of opioid antagonist, for example a level indicated by the composite model as having a desired level of efficacy.
  • parameters, including but not limited to EC20, EC50 and EC90, identified by the composite model may be employed to select desirable levels of plasma concentrations of opioid antagonist (as measured directly or via a sunogate marker such as 6 ⁇ -naltrexol).
  • Parameters provided by the composite model may be employed to select desirable doses of naltrexone from the plasma concentrations of 6 ⁇ -naltrexol, based on the . foregoing data, parameters and adjustments relating to 6 ⁇ -naltrexol.
  • the plasma concentration of 6 ⁇ -naltrexol is useful as an indicator of the absorption of naltrexone, since 6 ⁇ -naltrexol is generally present in plasma at concentrations much higher than those of naltrexone due to the rapid metabolism of naltrexone to yield 6 ⁇ -naltrexol.
  • a 6 ⁇ -naltrexol plasma concentration of about 0.4 pg/ml indicates a naltrexone plasma concentration of about 0.04 pg/ml in the plasma sample, and where a given 6 ⁇ -naltrexol plasma concentration is provided herein, a naltrexone plasma concentration of about 1/10 of the given 6 ⁇ -naltrexol plasma concentration is also contemplated.
  • the plasma concentration of 6 ⁇ -naltrexol at steady state is generally proportional to the dose amount of naltrexone in a B ID dosing regimen. It has been found that a dose of an opioid antagonist such as naltrexone given as a BID regimen that produces plasma concentrations of free 6 ⁇ -naltrexol that are related by a proportionality factor to naltrexone correlated for a given dose of an opioid agonist statistically (p ⁇ .001) with percent decreases in pain intensity from base line for moderate to severe pain.
  • an opioid antagonist such as naltrexone given as a BID regimen that produces plasma concentrations of free 6 ⁇ -naltrexol that are related by a proportionality factor to naltrexone correlated for a given dose of an opioid agonist statistically (p ⁇ .001) with percent decreases in pain intensity from base line for moderate to severe pain.
  • a desirable dose amount of opioid antagonist and optionally a desirable dose amount of opioid agonist, can be selected based on a steady state plasma concentration that exhibits a desired pharmacodynamic (PD) effect.
  • PD pharmacodynamic
  • Exemplary data for plasma concentrations and PD effects are shown in Table 25.
  • a formula for converting between concentration and dose can be established by experimentally determining plasma concentrations that result from known dose amounts. This formula may be used to select dose amounts of opioid antagonists converted from plasma concentrations showing a desired PD effect.
  • the dose of a co-administered opioid agonist may be adjusted, by increasing or decreasing the dose, relative to the opioid antagonist, to further optimize pain relief or other efficacy outcomes as described herein.
  • naltrexone as measured by its major metabolite 6 ⁇ -natrexol were too high in the OID dosing regimen, thus a statistically significant increase in pain relief with the QID dosing regimen of naltrexone as described herein was not achieved.
  • a statistically significant increase in pain relief with a similar QID dosage regimen of the opioid antagonist e.g., naltrexone
  • the opioid antagonist e.g., naltrexone
  • the opioid agonist e.g., oxycodone
  • Parameters including but not limited to EC20, EC50 and EC90, identified by the composite model may be employed to select desirable amounts of opioid antagonist in various dosage forms.
  • a desired amount of opioid antagonist can be determined from a selected plasma concentration arising from a known amount of opioid antagonist, since the relationship between concentration and dose amount is generally linearly proportional.
  • the plasma concentrations of 6 ⁇ naltrexol from randomly selected samples from subjects receiving 1 ⁇ g of naltrexone and 20 mg of oxycodone in a BID dosing regimen were fit to the Emax composite model.
  • the EC52 of 6 ⁇ naltrexol in the plasma as the surrogate marker for the active drug naltrexone in the plasma, corresponding to 1 ⁇ g of naltrexone from the BID dosing regimen was computed.
  • parameters provided by a composite model are useful for predicting doses from desirable lower levels of plasma concentrations of 6 ⁇ - naltrexol. More particularly, the EC52 parameter in Table 26 suggests that a 6 ⁇ -naltrexol plasma concentration of about 0.439 pg/ml or more may be employed to attain better than a 50% reduction in pain intensity. Additional preferences may be selected; for example, if one wishes to attain better than 20% or better than 90% reduction in pain intensity, one may select the plasma concentrations indicated in Figure 11 that correspond to the 20% or the 90% effectiveness levels, respectively.
  • parameters provided by the composite model are useful for selecting desirable higher levels of plasma concentrations of 6 ⁇ -naltrexol.
  • the EC51 parameter may be used in a fashion similar to the use of the EC52 parameter as described above.
  • a range of preferred dose amounts was calculated from the Emax composite model using EC20 derived from the graphic output and the sum of the EC52 plus the CN% obtained from the model. For example, a range of dose amounts is selected wherein the low point is the dose amount corresponding to the plasma concentration at EC20, and the high point is the dose amount corresponding to the plasma concentration that is the sum of the EC52 plus the CN% (133) obtained from the Emax composite model.
  • preferred dose amounts of opioid antagonist may comprise the range of from about 0.829 ⁇ g to about 2.37 ⁇ gs.
  • an alternative prefened dose amounts may comprise the range of from about 0.415 ⁇ g to about 1.19 ⁇ gs. It is contemplated that, generally, a preferred dose amount may be adjusted in a proportionate manner to a change in oxycodone amount. If oxycodone amount is reduced or increased by a factor of 2, 4, or 8 (or other factor), the end points of the prefened range are each reduced or increased by a same factor (2, 4, or 8 or other factor)).
  • the plasma concentration-effect data set forth above for the subjects receiving the BID dosing regimen or the total plasma concentration-effect data (QID and BID dosing regimens) can be employed to select dose amounts of opioid antagonist to be administered.
  • the plasma concentration-effect data in Table 27, which relate to the plasma concentration-effect data from subjects receiving the BID dosing regimen, and the mathematical evaluation of the data using the Emax composite model, as exemplified in Figure 12, may be employed to select dose amounts of opioid antagonist to be administered in a BID dosing regimen.
  • presently prefened dose amounts of opioid antagonist comprise from about 0.829 ⁇ g to about 2.37 ⁇ gs.
  • exemplary dose amounts of opioid antagonist are contemplated: 1 mg oxycodone per dose: from about 0.041 ⁇ g to about 0.119 ⁇ g opioid antagonist per dose 2.5 mg oxycodone per dose: from about 0.103 ⁇ g to about 0.297 ⁇ g opioid antagonist per dose 5 mg oxycodone per dose: from about 0.207 ⁇ g to about 0.593 ⁇ g opioid antagonist per dose 10 mg oxycodone per dose: from about 0.415 ⁇ g to about 1.19 ⁇ gs opioid antagonist per dose 40 mg oxycodone per dose: from about 1.66 ⁇ gs to about 4.74 ⁇ gs opioid antagonist per dose 80 mg oxycodone per dose: from about 3.32 ⁇ gs to about
  • the plasma concentration-effect data in Table 26 which relate to the total plasma concentration-effect data from subjects receiving the BID dosing regimen and subject receiving the QID dosing regimen, and the mathematical evaluation of the data using the composite Emax/Imax model, as exemplified in Figure 11, may be employed to select preferred dose amounts of opioid antagonist more generally.
  • presently prefened dose amounts of opioid antagonist comprise from about 0.830 ⁇ g to about 5.02 ⁇ gs.
  • exemplary dose amounts of opioid antagonist are contemplated: 1 mg oxycodone per dose: from about 0.041 ⁇ g to about 0.252 ⁇ g opioid antagonist per dose 2.5 mg oxycodone per dose: from about 0.104 ⁇ g to about 0.63 ⁇ g opioid antagonist per dose 5 mg oxycodone per dose: from about 0.208 ⁇ g to about 1.26 ⁇ g opioid antagonist per dose 10 mg oxycodone per dose: from about 0.415 ⁇ g to about 2.51 ⁇ gs opioid antagonist per dose 40 mg oxycodone per dose: from about 1.66 ⁇ gs to about 10.0 ⁇ gs opioid antagonist per dose 80 mg oxycodone per dose: from about 3.32 ⁇ gs to about 20.1 ⁇ gs opioid antagonist per dose 160 mg oxycodone per dose: from about 6.64 ⁇ gs to about 40.2 ⁇ gs opioid antagonist per dose
  • a BID dosing regimen that includes an amount of oxycodone per dose
  • any of the foregoing ranges may be broadened by substituting the foregoing lower ends with a lower end of about 0.0002 ⁇ g, since dose amounts as low as about 0.0002 ⁇ g are presently contemplated. It was observed that the lower end of the ranges can approach zero based on the relatively low CN%s observed at the low end of the composite model (i.e., the values 132 and 151 for the BID and total (BID and QID) data sets, respectively). This indicates that even lower dose amounts of naltrexone and other opioid antagonists would be expected to be active, and dose amounts of about 0.0002 ⁇ g would be expected to be active albeit in a decreasing proportion of the population.
  • the present Example also provides prefened methods and materials comprising opioid antagonists other than naltrexone, such as naloxone and nalmefene. It is believed that, generally, the prefened dose amounts of naltrexone calculated above are useful for other opioid antagonists. Persons skilled in the field will recognize a particular opioid antagonist may have potency, bioavailability, metabolism, clearance, or other characteristics that suggest an adjustment to the dose amount, dosage form, or dosing regimen.
  • opioid antagonists having reduce oral availability compared to naltrexone it is contemplated that a higher oral dose amount will be provided, or that a more frequent dosing regimen will be employed, or that an intravenous dose will be provided, or some other adjustment will be made. Such adjustments are well within the ability of persons skill in the field. [343] As discussed above, methods and materials are provided for titrating an opioid antagonist administered to a human subject.
  • a suitable method comprises the steps of (a) administering an amount of an opioid antagonist and an amount of an opioid agonist to the subject, (b) measuring a plasma concentration in the subject of the opioid antagonist or a sunogate of the opioid antagonist, and (c) adjusting the amount of the opioid antagonist administered to the subject if the measured plasma concentration is outside a predetermined plasma concentration range.
  • the predetermined plasma concentration range can be from concentrations predicted by a model of plasma concentration-effect relationship (e.g., the Emax composite model described above).
  • the predetermined plasma concentration range can be the range predicted by the model to provide a reduction in pain intensity of about 20% or greater, alternatively about 50% or greater, alternatively about 90% or greater.
  • the predetermined plasma concentration can be based on the plasma concentration-effect model shown in Figure 11 or Figure 12.
  • the present methods and materials for titrating an opioid antagonist administered to a human subject are not limited to the use of a composite model or to the use of predetermined plasma concentrations.
  • methods and materials of titrating an opioid antagonist administered to a human subject comprise (a) administering an amount of an opioid antagonist and an amount of an opioid agonist to the subject, (b) assessing one or more symptoms or signs of an artliritic condition, inflammation associated with a chronic condition, or chronic pain, (c) measuring a plasma concentration in the subject of the opioid antagonist or a sunogate of the opioid antagonist, and (d) adjusting the amount of the opioid antagonist or the amount of the opioid agonist to the subject based on the measured plasma concentration.
  • Step (d) may include comprises adjusting the amount of the opioid antagonist administered to the subject; alternatively or additionally, step (d) can comprises adjusting the amount of trie opioid agonist administered to the subject.
  • methods and materials of titrating an opioid antagonist administered to a human subject comprise (a) administering an amount of an opioid antagonist and an amount of an opioid agonist to the subject, (b) assessing one or more symptoms or signs of an arthritic condition, inflammation associated with a chronic condition, or chronic pain, and (c) adjusting 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 mamtaining the amount of the opioid agonist administered to the subject.
  • the method may also comprise the steps of (d) re-assessing one or more of the symptoms or signs after step (c), and (e) adjusting the amount of the opioid agonist if one or more of the assessed symptoms or signs are not alleviated to a desired extent.
  • it may be desirable to repeatedly administer the opioid antagonist such that a steady state is achieved before assessing one or more symptoms or signs of an arthritic condition, inflammation associated with a chronic condition, or chronic pain.
  • the initial step of administering a first amount of an opioid antagonist and/or a first amount an opioid agonist can be repeated if the measured plasma concentration is within the predetermined plasma concentration range and/or if the assessed symptom(s) or sign(s) is alleviated to a desired extent.
  • one or more of the assessed symptoms or signs may be pain, stiffness, and/or difficulty in physical function had by the subject, or measures of pain, stiffness and difficulty in physical function, such as the measures set forth in the WOMAC Osteoarthritis Index or one of its subscales.
  • a symptom or sign assessed for purposes of titration may be pain as measured as pain intensity.
  • the pain intensity measurement may be attenuated as compared to a pain intensity baseline measurement of the subject.
  • the pain intensity measurement may be reduced by at least about 20%, alternatively at least about 50%, alternatively at least about 90%, compared to a pain intensity baseline measurement of the subject.
  • a plasma concentration of the opioid antagonist or a sunogate of the opioid antagonist may be measured, and the amount of the opioid antagonist can be adjusted based in part on the measured plasma concentration. For example, the amount of the opioid antagonist administered to the subject is increased if the measured plasma concentration is lower than a predetermined plasma concentration value. As another example, the amount of the opioid antagonist administered to the subject is decreased in the measured plasma concentration is higher than a predetermined plasma concentration value. As yet another example, the amount of the opioid antagonist administered to the subject is maintained in the measured plasma concentration is within a predetermined plasma concentration range, and optionally the amount of the opioid agonist administered to the subject is increased.
  • opioid antagonists are contemplated for use with a wide variety of opioid agonists
  • particular concentrations and/or amounts may be selected based on the present disclosure.
  • the foregoing generally prefened concentrations and amounts have been selected based on data from clinical studies employing the opioid antagonist naltrexone and the opioid agonist oxycodone, however they are also contemplated for use with a wide variety of opioid antagonists and opioid agonists.
  • EXAMPLE 4 [350] A clinical study was conducted as described in Example 1 (Part A) and data were obtained as described in Examples 1 and 2. Plasma samples from selected subjects in the clinical study were used to assay for the presence and concentration of selected cytokines. [351] Plasma samples were analyzed using a commercial cytokine assay from Pointil Liste (www.pointil Liste.com) to quantify the concentrations of IL2, IL4, IL5, IL6, IL10, IL13, GM- CSF, interferon and TNF ⁇ . Plasma samples were separately analyzed for ILl ⁇ and ILl ⁇ , which were quantitated using a conventional cytokine assay by Pointilliste.
  • the cytokine assay for the quantitation of IL2, IL4, IL5, IL6, IL10, ELI 3, GM-CSF, interferon and TNF ⁇ employed, Pointil Liste's Human Thl/Th2 Cytokine Canvas product which contains binding sites for each of these nine cytokines.
  • the anay pattern of cytokine antibodies printed in each well of a 96 well microtiter plate is shown in Table 28. Table 28 Pattern of Human Thl/Th2 Cytokine Canvas
  • Two different 96 well plates were used, and each received a subsample of the aliquots at different dilutions.
  • Two dilutions (1 in 1 and 1 in 10) of each sample were assayed on two separate human Thl/Th2 cytokine canvases.
  • standard curves were generated for each dilution.
  • a mixture of 9 cytokines was run on each of the canvases and used to calculate a standard curve, which was used to determine the amount of each cytokine in the samples.
  • the standard curves were plotted with the signal intensity as a function of the cytokine concentration in ng/ml.
  • a CCD camera was used with Pointilliste's Canvas Analysis Tools software to generate data conesponding to cytokine concentrations.
  • Tables 29 through 31 show measurements of cytokine concentrations (ng/ml) obtained as described herein and data calculated from those measured concentrations.
  • OXY refers to the treatment group receiving oxycodone QID as described in Example 1
  • BID refers to the freatment group receiving the combination drug of oxycodone and naltrexone BID as described in Example 1
  • QID refers to the treatment group receiving the combination drag of oxycodone and naltrexone QID as described in Example 1
  • GM refers to granulocyte/macrophage colony stimulating factor
  • IFN refers to interferon gamma
  • TNF refers to tumor necrosis factor alpha
  • IL2 refers to interleukin 2
  • IL4 refers to interleukin 4
  • IL5 refers to interleukin 6
  • IL10
  • Table 29 shows the individual cytokine measurements obtained from each sample as identified by sample identification number. Accordingly, Table 29 shows all the cytokine measurements that were obtained for each sample.
  • Table 30 shows a compilation of the individual cytokine measurements obtained from the plasma samples. These measurements were used to determine the mean cytokine concentrations. The numbers of measurements for the various cytokines differ because different interferences affected samples and cytokine measurement within those samples differently.
  • the cytokine assay did not provide measurements 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 occunences of high background, excess heme, lipolysis, desiccation, and the lowest level of quantification (LLOQ) for ILL
  • LLOQ lowest level of quantification
  • the missing values for cytokine concentrations occuned randomly among the subjects, and the random occurrence of missing values is believed to not interfere with the accumulation of data. Accordingly the measurements which were obtained from the assay are believed to be meaningful.
  • Table 30 shows the differences in cytokine levels between the different treatment groups (OXY, BID and QID) in the clinical study.
  • Table 31 the means for each treatment group of the plasma concentrations of the various cytokines, along with the standard deviation for the measurements within the treatment groups.
  • the mean values for the cytokine concentrations detected for each plasma sample analyzed from the various treatment groups is set forth along with the standard deviation. The mean and standard deviation values were calculated using the duplicate values obtained from various plasma samples.
  • cytokines are appropriate biomarkers, including for the monitoring, detection, diagnosis and/or treatment of arthritic conditions, inflammation associated with a chronic condition and/or chronic pain. Such biomarkers are useful to detect anti-inflammatory activity or other effects of the present methods and materials. Biomarkers, such, as cytokines, are of interest to the pharmaceutical industry for various uses, including, for example, to determine potential activity of drugs in clinical development.
  • Solid oral dosage forms comprising opioid agonists and/or opioid antagonists can be prepared by a variety of processes well-known to those skilled in the art. For example, methods and materials as described in U.S. Patent Application Publication No. 2003/0191147 (previously incorporated by reference herein) and WO 01/85257 (PCT/US01/14377) are useful in preparing dosage forms comprising opioid agonists and/or opioid antagonists, including wherein the dosage form comprises amounts of opioid antagonists of 1 mg or less.
  • solid oral dosage forms comprising oxycodone hydrochloride (OXY) and naltrexone hydrochloride (NTX) are prepared as described herein. For clinical studies as described in Example 1, tablets having different amounts of oxycodone were manufactured, though the amount of naltrexone was the same (0.001 mg) among the tablets of different strength.
  • the wet granulation was sieved in a wet sizing step through a mesh screen and dried in a fluidized bed to an endpoint moisture content of not more than 3 percent determined by a Loss on Drying (LOD) measurement.
  • LOD Loss on Drying
  • Tablets were film coated in a perforated pan that included application of a clear base coating followed by an aesthetic color coating.
  • a commercially available clear coating (Colorcon-Opadry Clear) was applied to achieve an average coating weight of 2 ⁇ 0.4 mg per tablet.
  • a commercially available color coating (Colorcon-Opadry II Yellow) was applied to achieve an average coating weight of approximately 8 ⁇ 1 mg per tablet.
  • Table 33 sets forth the composition of exemplary 2.5 mg strength tablets (tablets comprising 2.5 mg oxycodone HCl and 0.001 mg naltrexone hydrochloride).
  • Table 34 sets forth the composition of exemplary 5 mg strength tablets (tablets comprising 5 mg oxycodone HCl and 0.001 mg naltrexone hydrochloride).
  • Table 35 sets forth the composition of exemplary 7.5 mg sfrength tablets (tablets comprising 7.5 mg oxycodone HCl and 0.001 mg nalfrexone hydrochloride).
  • Table 36 sets forth the composition of exemplary 10 mg sfrength tablets (tablets comprising 10 mg oxycodone HCl and 0.001 mg naltrexone hydrochloride).
  • Table 37 sets forth the composition of exemplary 15 mg sfrength tablets (tablets comprising 15 mg oxycodone HCl and 0.001 mg nalfrexone hydrochloride).
  • Table 38 sets forth the composition of exemplary 20 mg sfrength tablets (tablets comprising 20 mg oxycodone HCl and 0.001 mg naltrexone hydrochloride).
  • An advantage of dosage forms prepared as referenced and described in this example, including tablets made by the procedure described above and summarized in Figure 13 is that undesirable binding of the opioid antagonist to the excipients is essentially avoided. It was previously noted that some opioid antagonists undesirably bind significantly to certain pharmaceutical excipients in an environment of use (see, e.g., WO 01/85257 (PCT/USOl/14377) and U.S. Patent Application Publication No. 2003/0191147). Undesirable binding generally causes an incomplete amount of the opioid antagonist to be released from a dosage form, within a particular time allotted for release in a dissolution test or in clinical use.
  • the use of an acidic pH during the wet granulating step was advantageous with respect to avoiding undesirable binding.
  • the wet granulation step employed a granulation solution having a pH adjusted to 3.5 with citric acid.
  • the tablets manufactured by this manufacturing process did not exhibit undesirable binding of the opioid antagonist and the excipients to a significant degree.
  • some embodiments of the present methods and materials include steps or excipients which reduce or minimize undesirable binding of opioid antagonist and one or more pharmaceutical excipients, so that such excipients do not bind the opioid antagonist to a significant degree hi an environment of use.

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Abstract

La présente invention concerne des procédés et produits, et notamment de nouvelles compositions des formes posologiques, et des procédés d'administration, convenant particulièrement au traitement d'états arthritiques, d'inflammation associée à un état chronique et/ou une douleur chronique, et notamment la douleur d'origine arthritique et inflammatoire, par utilisation d'antagonistes d'opioïdes, et notamment des combinaisons d'antagonistes et d'agonistes d'opioïdes. Les procédés et des produits comprenant des antagonistes d'opioïdes ou des combinaisons d'antagonistes et d'agonistes d'opioïdes peuvent également comporter un ou plusieurs agents thérapeutiques supplémentaires.
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