USO080 12990B2

(12) United States Patent (10) Patent No.: US 8,012,990 B2 Richards et al. (45) Date of Patent: *Sep. 6, 2011

(54) METHODS OF CONVERTING A PATIENTS McPherson (Demystifying Opioid Conversion Calculations: A TREATMENT REGIMIEN FROM Guide for Effective Dosing, Publication date Aug. 25 2009).* INTRAVENOUS ADMINISTRATION OF AN Alberta Hospice document (Alberta Hospice Palliative Care OPOD TO ORAL CO-ADMINISTRATION OF Resource Manual 2001).* Embeda R. Prescribing Information, Jun. 2009. MORPHINE AND OXYCODONE USINGA Morphine Sulfate Prescribing Information Mar. 2008. DOSING ALGORTHM TO PROVIDE Oxycontin R. Prescribing Information Apr. 16, 2010. ANALGESA Opana R. Prescribing Information, 2006. Chevlen E. J. Pain Symptom. Manag., 19:1 (2000) S42-9. (75) Inventors: Patricia T. Richards, Bedminster, NJ Ross et al., Pain 84 (2000) 421-28. (US); Warren C. Stern, Bedminster, NJ Riley et al., Eur: J. Pain Suppl. 1 (2007) 23-30. (US); Laurel J. Mengle-Gaw, St. Louis, Riley et al., Support Care Cancer 14 (2006) 56-64. MO (US); Benjamin D. Schwartz, St. Mercadante et al., Cancer, 95 (2002) 203-08. Louis, MO (US) Mercadante et al., Cancer Treatment Reviews 32 (2006) 304-15. Mercadante, S., Eur: J. Pain 11 (2007) 823-30. (73) Assignee: QRxPharma Ltd., Bedminster, NJ (US) Holaday et al., Perioperative Medizin, 1:4 (2009) 244. Kotlinska-Lemieszek, A. J. Pain Symptom. Manag., 40:1 (2010) e10-e12. (*) Notice: Subject to any disclaimer, the term of this Ladd et al., Br: J. Clin. Pharmacol., 59:5 (2005) 524-35. patent is extended or adjusted under 35 Grach et al., Br: J. Clin. Pharmacol., 58:3 (2004) 235-42. U.S.C. 154(b) by 0 days. Smith et al., Br. J. Clin. Pharmacol., 59:4 (2005) 486-87. Anderson et al..J. Pain Symptom Manag., 21:5 (2001) 397-406 This patent is Subject to a terminal dis (“Anderson”). claimer. Lichtor et al...Anesth. Analg. 89 (1999) 732-38. Foley, K., N. Engl. J. Med., 313:2 (1985) 84-95. (21) Appl. No.: 12/881,728 Richards et al., J. Pain 10:4 (2009) S49; Richards et al., Two Explor atory Double-Blinded Crossover Studies of the Treatment of Chronic (22) Filed: Sep. 14, 2010 Noncancer Pain. Eficacy and Safety of Concurrent Dosing of Mor phine Plus Oxycodone vs Morphine Alone. 2009 Annual Meeting of (65) Prior Publication Data the Americal Pain Society, May 7-9, 2009, San Diego, CA. Webster et al., J. Pain 11:4 (2010) S50. US 2011 FOO86874 A1 Apr. 14, 2011 Webster et al., J. Pain 11:4 (2010) S51. Webster et al., J. Pain 11:4 (2010) S53. Webster et al., Single-Dose Related U.S. Application Data and Steady-State Pharmacokinetics of MaxDuOR, a Dual Opioid Formulation Containing a Fixed Ratio of Morphine and Oxycodone. (63) Continuation-in-part of application No. 12/579,173, 29' Annual Meeting of the America Pain Society, May 68, 2010, filed on Oct. 14, 2009, now abandoned. Baltimore, MD. www.palliative.org/PC/Clinicallnfo/AssessmentTools/ (51) Int. Cl. MeanEquivalent%20for%20program%20v3.pdf, Jul. 26, 2010. AOIN 43/42 (2006.01) www.QRXPharma.com, Press Release, Sep. 1, 2010. AOIN 43/38 (2006.01) www.QRXPharma.com, Press Release, Aug. 17, 2010. AOIN37/10 (2006.01) www.QRXPharma.com, Press Release, May 4, 2010. A6 IK3I/44 (2006.01) www.QRXPharma.com, Press Release, Apr. 14, 2010. A6 IK3I/40 (2006.01) (Continued) A6 IK 9/28 (2006.01) A6 IK9/20 (2006.01) Primary Examiner — Sreeni Padmanabhan CO7D 489/00 (2006.01) Assistant Examiner — Uma Ramachandran A6 IK3I/9 (2006.01) (74) Attorney, Agent, or Firm — Frommer Lawrence & (52) U.S. Cl...... 514/282:546/44; 514/420; 514/568; Haug LLP; Sandra Kuzmich; Russell A. Garman 424/474; 424/468 (58) Field of Classification Search ...... 514/282, (57) ABSTRACT 514/.420, 568; 546/44; 424/474, 468 A method of converting a treatment for pain comprising intra See application file for complete search history. venous administration of opioids, to a treatment for pain comprising oral administration of a first dose of an immediate (56) References Cited release morphine-oxycodone combination in patients in need of analgesia. The method may comprise (1) determining a U.S. PATENT DOCUMENTS four-hour average oral morphine equivalents or determining a 6,310,072 B1 10/2001 Smith et al. 2005.0053659 A1 3/2005 Pace et al. net average hourly intravenous dose, and (2) orally adminis 2008, OO394.63 A1 2/2008 Nadeson et al. tering to the patient a first dose of a morphine-oxycodone 2009,029 1975 A1 11, 2009 Stern et al. combination in a 3:2 ratio by weight every four to six hours. Also, a method of treating pain in patients who had been FOREIGN PATENT DOCUMENTS administered opioids intravenously, comprising using a dos WO 2010/085848 8, 2010 ing algorithm to determine the first dose of the immediate OTHER PUBLICATIONS release morphine-oxycodone combination. Kerri Wachter (Internal Medicine News, 2008).* 12 Claims, No Drawings US 8,012,990 B2 Page 2

OTHER PUBLICATIONS www.QRXPharma.com, Press Release, May 22, 2008. www.QRXPharma.com, Press Release, Mar. 30, 2010. www.QRXPharma.com, Press Release, May 5, 2008. Notification of Transmittal of the International Search Report and the www.QRXPharma.com, Press Release, Feb. 10, 2010. Written Opinion of the International Searching Authority, or the www.QRXPharma.com, Press Release, Nov.30, 2009. Declaration, Patent Cooperation Treaty, Dec. 30, 2009, PCT/US09/ www.QRXPharma.com, Press Release, Aug. 26, 2009. 62917. www.QRXPharma.com, Press Release, Apr. 20, 2009. * cited by examiner US 8,012,990 B2 1. 2 METHODS OF CONVERTING A PATIENTS ptive doses of morphine with sub-antinociceptive doses of TREATMENT REGIMEN FROM oxycodone were similar to placebo-injected control animals INTRAVENOUS ADMINISTRATION OF AN with respect to CNS side effects. Seeid at 424-25. Animals OPOD TO ORAL CO-ADMINISTRATION OF that received equipotent doses of either opioid alone were MORPHINE AND OXYCODONE USINGA 5 more sedated as compared to the control animals. Seeid at DOSING ALGORTHM TO PROVIDE 425-26. ANALGESA Synergistic analgesic effects of orally co-administering morphine and oxycodone at a 3:2 ratio have been demon CROSS REFERENCE TO RELATED strated in patients (see, e.g., U.S. Pat. No. 6,310,072 and U.S. APPLICATION 10 Publication Nos. 2005/0053659, 2007/0031489, 2009/ 0291975 and U.S. application Ser. No. 12/567.209). How This application is a continuation-in-part of U.S. patent ever, efficacy of treating pain by co-administering morphine application Ser. No. 12/579,173, filed on Oct. 14, 2009 now and oxycodone is dependent, at least in part, on the quantity abandoned. that is administered. For example, administration of a dosage 15 of morphine and oxycodone will not produce analgesia if the FIELD OF THE INVENTION quantity administered is too low. The quantity of morphine and oxycodone administered may also play a role in the The present invention relates to treatment of pain in occurrence of side effects that are common to opioids, such as patients. In certain aspects, the present invention is directed to nausea, vomiting, drowsiness, dizziness, mental clouding, a method of converting a patient’s pain treatment regimen dysphoria, pruritus, constipation, increased biliary tract pres from intravenous (IV) administration of an opioid to an orally Sure, urinary retention, hypotension, respiratory depression administered combination of morphine and oxycodone in a and bladder dysfunction. Moreover, the onset of tolerance to weight ratio of about 3:2. This method may include the use of the therapeutic effects of the drugs, as well as the initiation of a dosing algorithm for determining an appropriate dosage of physical dependence, may occur with daily administration of the morphine and oxycodone combination. 25 opioids; the extent of such tolerance or physical dependence is dependent in part on the quantity of opioids administered. BACKGROUND OF THE INVENTION Therefore, it is important to determine an effective oral dos ing regimen for co-administering morphine and oxycodone in Patients who experience significant pain as the result of, for order to effectively and safely treat pain. example, a serious traumatic injury, a Surgical procedure, or 30 The determination of the appropriate quantity of morphine chronic illness (e.g., cancer), require relief through strong and oxycodone to administer is especially important for prescription medication. Opiate drugs are a class of pain patients recovering from a serious traumatic injury or a Sur relieving prescription medications frequently used in the gical procedure. These patients are often treated for pain treatment of a variety of acute and chronic, moderate to initially by IV administration of an opioid drug such as mor severe, pain. Examples include natural opiates such as mor 35 phine. Once these patients leave the hospital or Surgical center phine, codeine, and thebaine; semi-synthetic opioids such as and are no longer under medical Supervision, they must hydromorphone, hydrocodone, oxycodone, oxymorphone, receive the opioid drugs by a different route (e.g., orally) diacetylmorphine (heroin), nicomorphine, dipropanoylmor since repeated IV dosing is no longer practical. In the past, phine, benzylmorphine, ethylmorphine, buprenorphine and doctors have often estimated the necessary oral dose of some morphine glucuronides (including the 3- and 6-glucuronide); 40 drugs following IV administration, but such practice often and fully synthetic opioids such as alfentanil, fentanyl. results in either over-medication, which can lead to adverse remifentanil, Sufentanil, trefentanil, pethidine, methadone, side effects, or under-medication, which can result in ineffec tramadol and dextropropoxyphene. tive pain management. Also, physicians often consult equi The World Health Organization's guidelines recommend analgesic tables before opioid rotation or conversion to deter that two strong opioids should not be co-administered, pre 45 mine a new safe starting dose appropriate for adequate pain Sumably because it is generally thought that all opioids exert control. Unfortunately, there are wide and clinically impor their analgesic effects through the same receptor mechanisms tant differences in published opioid equianalgesic ratios. See in the central nervous system (CNS). See World Health Orga Shaheen et al., J. Pain Symptom. Manag., 38.3 (2009) 409-16. nization, Cancer Pain Relief and Palliative Care, Geneva: Thus, there is a need for a method of converting doses of WHO 1990. Studies have shown, however, that the antinoci 50 intravenously administered opioids to an oral opioid dose that ceptive (also termed analgesic) effects of structurally related effectively manages the patient’s pain and at the same time morphine and oxycodone are differentially antagonized by reduces or eliminates the problems associated with over- or naloxonazine (a selective u-opioid receptor antagonist) and under-medication. In particular, there is a need for a method nor-BN1 (a K-selective opioid antagonist), respectively, indi of converting doses of intravenously administered opioid to cating that they produce antinociception through different 55 orally co-administered morphine-oxycodone combination in opioid receptor mechanisms. See Ross et al., Pain 1997. 73, a weight ratio of about 3:2 151-57. The opioid receptor is believed to have four receptor subtypes named u-opioid receptor (MOR), O-opioid receptor SUMMARY OF THE INVENTION (SOR), K-opioid receptor (KOR) and 6-opioid receptor (DOR). The biochemical and cellular effects of morphine are 60 The present invention provides a method of treating pain in mediated through the MOR, found in high density within the patients. In particular, the method addresses the need to con CNS. vert the treatment regimen of patients who were receiving IV It has been found that co-administration to rats of Sub administration of an opioid in the hospital or Surgical center, antinociceptive (also termed Sub-analgesic) doses of mor to oral doses of opioids, such as when IV dosing is no longer phine with Sub-antinociceptive doses of oxycodone results in 65 practical or appropriate to administer. synergistic levels of antinociception. See Ross et al., Pain One aspect of the present invention is directed to a method 2000, 84, 421-28. Animals that received the sub-antinocice of converting a treatment for pain comprising IV administra US 8,012,990 B2 3 4 tion of an opioid to a treatment for pain comprising oral morphine-oxycodone combination is about 18 mg of mor co-administration of an immediate release morphine-oxyc phine, or a pharmaceutically acceptable salt thereof, and odone combination (i.e., morphine, or a pharmaceutically about 12 mg of oxycodone, or a pharmaceutically acceptable acceptable salt thereof, and oxycodone, or a pharmaceutically salt thereof. Further, if the four-hour average oral morphine acceptable salt thereof) in a weight ratio of about 3:2, in a equivalent dose is greater than about 40 mg and less than or human patient in need of analgesia, such that the method may equal to about 120 mg. then the first dose of the morphine comprise determining a four-hour average oral morphine oxycodone combination is about 24 mg of morphine, or a equivalent dose of the opioid administered intravenously to pharmaceutically acceptable salt thereof, and about 16 mg of the human patient, and orally co-administering to the human oxycodone, or a pharmaceutically acceptable salt thereof. patient a first dose of an immediate release morphine-oxyc 10 In some embodiments, the four-hour average oral mor odone combination in accordance to a dosing algorithm. phine equivalent dose is determined by Equation (1): Applying a dosing algorithm according to some embodi ments of the invention, if the four-hour average oral morphine equivalent dose is between about 0 mg and about 30 mg, then 4-Hour Average (1) the first dose of the morphine-oxycodone combination is no 15 X 4) XbXS greater than about 12 mg of morphine, or a pharmaceutically Oral Morphine = h - 4 acceptable Salt thereof, and about 8 mg of oxycodone, or a Equivalent Dose pharmaceutically acceptable salt thereof. If the four-hour average oral morphine equivalent dose is greater than about wherein m total amount (mg) of oral morphine equivalents 30 mg and less than or equal to about 40 mg. then the first dose of the opioid used during IV administration (including bolus of the morphine-oxycodone combination is about 18 mg of and PCA); n-oral morphine equivalents (mg) of the opioid morphine, or a pharmaceutically acceptable salt thereof, and used during the first four hours of IV administration; h=total about 12 mg of oxycodone, or a pharmaceutically acceptable time (hour) that the oral morphine equivalents of the opioid salt thereof. Further, if the four-hour average oral morphine was administered intravenously: b clinical bioeduivalency equivalent dose is greater than about 40 mg and less than or 25 factor; and s=safety factor. equal to about 120 mg. then the first dose of the morphine In some embodiments, for the various opioids adminis oxycodone combination is about 24 mg of morphine, or a tered intravenously, the clinical bioequivalency factor is pharmaceutically acceptable salt thereof, and about 16 mg of between about 1 and about 15. In other embodiments, the oxycodone, or a pharmaceutically acceptable salt thereof. clinical bioeduivalency factor is about 2. In some embodi In some embodiments, if the four-hour average oral mor 30 ments, the safety factor is between about 0.50 and about 1.0. phine equivalent dose is between about 0 mg and about 30 In other embodiments, the safety factor is about 0.75. mg, then the first dose of the morphine-oxycodone combina Another aspect of the present invention is directed to a tion is about 12 mg of morphine, or a pharmaceutically method of converting a treatment for pain comprising IV acceptable Salt thereof, and about 8 mg of oxycodone, or a administration of morphine, or a pharmaceutically acceptable pharmaceutically acceptable salt thereof. 35 salt thereof, to a treatment for pain comprising oral co-admin In certain embodiments, if the four-hour average oral mor istration of an immediate release morphine-oxycodone com phine equivalent dose is between about 0 mg and about 10 bination (i.e., morphine, or a pharmaceutically acceptable salt mg, then the first dose of the morphine-oxycodone combina thereof, and oxycodone, or a pharmaceutically acceptable salt tion is about 3 mg of morphine, or a pharmaceutically accept thereof) in a weight ratio of about 3:2, in a human patient in able salt thereof, and about 2 mg of oxycodone, or a pharma 40 need of analgesia, Such that the method may comprise deter ceutically acceptable salt thereof. If the four-hour average mining a net average hourly IV morphine dose, and orally oral morphine equivalent dose is greater than about 10 mg and co-administering to the human patient a first dose of an imme less than or equal to about 15 mg. then the first dose of the diate release morphine-oxycodone combination in accor morphine-oxycodone combination is about 6 mg of mor dance to an algorithm. Applying a dosing algorithm accord phine, or a pharmaceutically acceptable salt thereof, and 45 ing to some embodiments of the invention, if the net average about 4 mg of oxycodone, or a pharmaceutically acceptable hourly IV morphine dose is between about 0 mg and about 9 salt thereof. If the four-hour average oral morphine equivalent mg, then the first dose of the morphine-oxycodone combina dose is greater than about 15 mg and less than or equal to tion is no greater than about 12 mg of morphine, or a phar about 20 mg, then the first dose of the morphine-oxycodone maceutically acceptable salt thereof, and about 8 mg of oxy combination is about 9 mg of morphine, or a pharmaceuti 50 codone, or a pharmaceutically acceptable salt thereof. If the cally acceptable salt thereof, and about 6 mg of oxycodone, or net average hourly IV morphine dose is greater than about 9 a pharmaceutically acceptable salt thereof. If the four-hour mg and less than or equal to about 14 mg. then the first dose average oral morphine equivalent dose is greater than about of the morphine-oxycodone combination is about 18 mg of 20 mg and less than or equal to about 30 mg. then the first dose morphine, or a pharmaceutically acceptable salt thereof, and of the morphine-oxycodone combination is about 12 mg of 55 about 12 mg of oxycodone, or a pharmaceutically acceptable morphine, or a pharmaceutically acceptable salt thereof, and salt thereof. Finally, if the net average hourly IV morphine about 8 mg of oxycodone, or a pharmaceutically acceptable dose is greater than about 14 mg. then the first dose of the salt thereof. morphine-oxycodone combination is about 24 mg of mor Applying a dosing algorithm according to Some embodi phine, or a pharmaceutically acceptable salt thereof, and ments of the invention, if the four-hour average oral morphine 60 about 16 mg of oxycodone, or a pharmaceutically acceptable equivalent dose is between about 0 mg and about 30 mg, then salt thereof. the first dose of the morphine-oxycodone combination is In some embodiments, if the net average hourly IV mor about 12 mg of morphine, or a pharmaceutically acceptable phine dose is between about 0 mg and about 9 mg, then the salt thereof, and about 8 mg of oxycodone, or a pharmaceu first dose of the morphine-oxycodone combination is about tically acceptable salt thereof. If the four-hour average oral 65 12 mg of morphine, or a pharmaceutically acceptable salt morphine equivalent dose is greater than about 30 mg and less thereof, and about 8 mg of oxycodone, or a pharmaceutically than or equal to about 40 mg. then the first dose of the acceptable salt thereof. US 8,012,990 B2 5 6 In some embodiments, if the net average hourly IV mor In some embodiments, the morphine-oxycodone combina phine dose is between about 0 mg and about 3 mg. then the tion may be co-administered in a single dosage form. In other first dose of the morphine-oxycodone combination is about 3 embodiments, the morphine-oxycodone combination may be mg of morphine, or a pharmaceutically acceptable salt co-administered in separate dosage forms. thereof, and about 2 mg of oxycodone, or a pharmaceutically 5 In some embodiments, the IV opioid comprises morphine, acceptable salt thereof. If the net average hourly IV morphine codeine, thebaine, hydromorphone, hydrocodone, oxyc dose is greater than about 3 mg and less than or equal to about odone, oxymorphone, diacetylmorphine (heroin), nicomor 5 mg, then the first dose of the morphine-oxycodone combi phine, dipropanoylmorphine, benzylmorphine, ethylmor nation is about 6 mg of morphine, or a pharmaceutically phine, buprenorphine and morphine glucuronides (including acceptable Salt thereof, and about 4 mg of oxycodone, or a 10 the 3- and 6-glucuronide), alfentanil, fentanyl, remifentanil, pharmaceutically acceptable salt thereof. If the net average Sufentanil, trefentanil, pethidine, methadone, tramadol, dex hourly IV morphine dose is greater than about 5 mg and less tropropoxyphene, a pharmaceutically acceptable salt thereof, than or equal to about 7 mg, then the first dose of the mor or a combination thereof. phine-oxycodone combination is about 9 mg of morphine, or In certain embodiments, the IV opioid comprises morphine a pharmaceutically acceptable Salt thereof, and about 6 mg of 15 or oxycodone or a pharmaceutically acceptable salt thereof. oxycodone, or a pharmaceutically acceptable salt thereof. If In certain embodiments, the method may further comprise the net average hourly IV morphine dose is greater than about orally co-administering one or more Subsequent doses of 7 mg and less than or equal to about 9 mg, then the first dose morphine-oxycodone combination about every four to six of the morphine-oxycodone combination is about 12 mg of hours, wherein the Subsequent doses comprise the same morphine, or a pharmaceutically acceptable salt thereof, and amount of morphine, or a pharmaceutically acceptable salt about 8 mg of oxycodone, or a pharmaceutically acceptable thereof, and oxycodone, or a pharmaceutically acceptable salt salt thereof. thereof, as the first dose. Applying a dosing algorithm according to certain embodi In various embodiments, if the patient has inadequate pain ments of the present invention, if the net average hourly IV relief, then the method may further comprise orally co-ad morphine dose is between about 0 mg and about 9 mg, then 25 ministering one or more Subsequent doses of morphine-oxy the first dose of the morphine-oxycodone combination is codone combination about every four to six hours, under the about 12 mg of morphine, or a pharmaceutically acceptable following conditions: if the first dose is about 3 mg of mor salt thereof, and about 8 mg of oxycodone, or a pharmaceu phine, or a pharmaceutically acceptable salt thereof, and tically acceptable salt thereof. If the net average hourly IV about 2 mg of oxycodone, or a pharmaceutically acceptable morphine dose is greater than about 9 mg and less than or 30 salt thereof, then the first subsequent dose is about 6 mg of equal to about 14 mg. then the first dose of the morphine morphine, or a pharmaceutically acceptable salt thereof, and oxycodone combination is about 18 mg of morphine, or a about 4 mg of oxycodone, or a pharmaceutically acceptable pharmaceutically acceptable salt thereof, and about 12 mg of salt thereof; if the first dose is about 6 mg of morphine, or a oxycodone, or a pharmaceutically acceptable salt thereof. If pharmaceutically acceptable salt thereof, and about 4 mg of the net average hourly IV morphine dose is greater than about 35 oxycodone, or a pharmaceutically acceptable salt thereof, 14 mg. then the first dose of the morphine-oxycodone com then the first Subsequent dose is about 9 mg of morphine, or a bination is about 24 mg of morphine, or a pharmaceutically pharmaceutically acceptable salt thereof, and about 6 mg of acceptable salt thereof, and about 16 mg of oxycodone, or a oxycodone, or a pharmaceutically acceptable salt thereof; if pharmaceutically acceptable salt thereof. the first dose is about 9 mg of morphine, or a pharmaceuti In one aspect of the present invention, the net average 40 cally acceptable salt thereof, and about 6 mg of oxycodone, or hourly IV morphine dose may be determined by (i) calculat a pharmaceutically acceptable salt thereof, then the first sub ing a net amount of morphine (or a pharmaceutically accept sequent dose is about 12 mg of morphine, or a pharmaceuti able salt thereof) administered intravenously to the human cally acceptable salt thereof, and about 8 mg of oxycodone, or patient, wherein the net amount is the total amount of mor a pharmaceutically acceptable salt thereof; if the first dose is phine administered intravenously to the human patient minus 45 about 12 mg of morphine, or a pharmaceutically acceptable the amount of morphine administered intravenously to the salt thereof, and about 8 mg of oxycodone, or a pharmaceu human patient during the first four hours of administration; tically acceptable salt thereof, then the first subsequent dose is (ii) calculating a net time that morphine was administered about 18 mg of morphine, or a pharmaceutically acceptable intravenously to the human patient, wherein the net time is the salt thereof, and about 12 mg of oxycodone, or a pharmaceu total time that morphine was administered intravenously 50 tically acceptable salt thereof; and if the first dose is about 18 minus four hours; and (iii) dividing the net amount of mor mg of morphine, or a pharmaceutically acceptable salt phine administered intravenously to the human patient by the thereof, and about 12 mg of oxycodone, or a pharmaceuti net time that morphine was administered intravenously to the cally acceptable salt thereof, then the first subsequent dose is human patient. about 24 mg of morphine, or a pharmaceutically acceptable In certain embodiments, the pharmaceutically acceptable 55 salt thereof, and about 16 mg of oxycodone, or a pharmaceu salt may be a hydrochloride, hydrobromide, hydroiodide, tically acceptable salt thereof. Sulfate, bisulfate, nitrate, citrate, tartrate, bitartrate, phos In certain embodiments, if the patient experiences, for phate, malate, maleate, napsylate, fumarate. Succinate, example, adverse effects with the first dose, then the method acetate, terephthalate, pamoate or pectinate. may further comprise orally co-administering one or more In particular embodiments, the morphine-oxycodone com 60 Subsequent doses of morphine, or a pharmaceutically accept bination comprises morphine Sulfate and oxycodone hydro able salt thereof, and oxycodone, or a pharmaceutically chloride. acceptable salt thereof about every four to six hours, under the In some embodiments, the morphine-oxycodone combina following conditions: if the first dose is about 24 mg of tion may be in an immediate release dosage form, Sustained morphine, or a pharmaceutically acceptable salt thereof, and release dosage form, or controlled release dosage form. In 65 about 16 mg of oxycodone, or a pharmaceutically acceptable particular embodiments, the morphine-oxycodone combina salt thereof, then the first subsequent dose is about 18 mg of tion may be in an immediate release dosage form. morphine, or a pharmaceutically acceptable salt thereof, and US 8,012,990 B2 7 8 about 12 mg of oxycodone, or a pharmaceutically acceptable As used herein in the context of a number, or a range of salt thereof; if the first dose is about 18 mg of morphine, or a numbers, “about will be understood to embrace somewhat pharmaceutically acceptable salt thereof, and about 12 mg of larger or Smaller values than the indicated value to account oxycodone, or a pharmaceutically acceptable salt thereof, for, as examples, experimental errors inherent in the measure then the first Subsequent dose is about 12 mg of morphine, or 5 ment and variability between different methodologies for a pharmaceutically acceptable Salt thereof, and about 8 mg of measuring the value, as will be apparent to one skilled in the oxycodone, or a pharmaceutically acceptable salt thereof; if art. the first dose is about 12 mg of morphine, or a pharmaceuti Methods of Converting Patients from IV Administration of cally acceptable salt thereof, and about 8 mg of oxycodone, or Opioids a pharmaceutically acceptable salt thereof, then the first sub 10 Embodiments of the present invention relate to a method of sequent dose is about 9 mg of morphine, or a pharmaceuti converting a treatment for pain comprising IV administration cally acceptable salt thereof, and about 6 mg of oxycodone, or of an opioid to a treatment for pain comprising oral co a pharmaceutically acceptable salt thereof; if the first dose is administration of a first dose of immediate release morphine about 9 mg of morphine, or a pharmaceutically acceptable and oxycodone, or pharmaceutically acceptable salts thereof, salt thereof, and about 6 mg of oxycodone, or a pharmaceu 15 in patients in need of analgesia. tically acceptable salt thereof, then the first subsequent dose is In certain embodiments, the IV administration of opioids about 6 mg of morphine, or a pharmaceutically acceptable may be by PCA. In some embodiments, the opioid adminis salt thereof, and about 4 mg of oxycodone, or a pharmaceu tered intravenously may be any compound, such as a drug, tically acceptable salt thereof; and if the first dose is about 6 that binds to opioid receptors. Examples of an opioid include, mg of morphine, or a pharmaceutically acceptable salt but are not limited to, morphine, oxycodone, codeine, hydro thereof, and about 4 mg of oxycodone, or a pharmaceutically codone, diamorphine, fentanyl, alfentanyl, buprenorphine, acceptable salt thereof, then the first subsequent dose is about hydromorphone, methadone, and oxymorphone. 3 mg of morphine, or a pharmaceutically acceptable salt A dosing algorithm may be used to determine the first oral thereof, and about 2 mg of oxycodone, or a pharmaceutically 25 immediate release dose of the morphine-oxycodone combi acceptable salt thereof. nation. In some embodiments, a four-hour average oral mor These and other objects, features and advantages of the phine equivalent dose may be initially calculated based on the present invention will become apparent after a review of the conditions of the IV administration of opioids, after which the following detailed description. first dose of the morphine-oxycodone combination is deter 30 mined. DETAILED DESCRIPTION The four-hour average oral morphine equivalent dose may be determined using Equation (1): The present invention relates to a method of converting a treatment for pain comprising IV administration of an opioid, to a treatment for pain comprising oral co-administration of a 35 4-Hour Average (1) first dose of an immediate release morphine-oxycodone com Oral Morphine = ( it - i. bination. The present invention also relates to a method of h - 4 treating pain in patients who had been treated with IV admin Equivalent Dose istration of opioids, comprising converting the patients to a treatment comprising oral co-administration of a first dose of 40 wherein m total amount (mg) of oral morphine equivalents an immediate release morphine-oxycodone combination. of the opioid used during IV administration (including bolus As used herein, “morphine' or “oxycodone recited sepa and PCA); n-oral morphine equivalents (mg) of the opioid rately refers to the free base forms of morphine or oxycodone, used during the first four hours of IV administration; h=total respectively. time (hour) that the oral morphine equivalents of the opioid As used herein, “pharmaceutically acceptable salt” refers 45 was administered under IV administration; b=clinical to a salt that is toxicologically safe for human and animal bioeduivalency factor, and S-Safety factor. administration. The term, "net amount of oral morphine equivalents As used herein, "morphine-oxycodone combination' administered,” may be used to describe the oral morphine refers to a combination of morphine, or a pharmaceutically equivalents used during IV administration, minus the oral acceptable salt thereof, and oxycodone, or a pharmaceutically 50 morphine equivalents used during first four hours of IV acceptable salt thereof. administration (m-n). The term, “net time administered.” As used herein, “morphine equivalent dose” refers to a may be used to describe the total hours that the oral morphine calculation of the amount of morphine that produces the same equivalents was administered IV less four hours (h-4). “Net analgesic effects as a particular amount of another opioid for average hourly intravenous dosing is therefore the net given route(s) of dose administration. For example, the oral 55 amount of oral morphine equivalents administered divided by morphine equivalent dose of 1 mg of oral oxycodone is 1.5 the net time administered. mg of oral morphine; in other words, 1 mg of oxycodone In Equation 1, the calculation of (m-n) and (h-4) essen administered orally will provide the same analgesic effect as tially exempts from the ultimate determination the opioid 1.5 mg of morphine administered orally. given during the first four hours of intravenous administra As used herein, “administration concurrently or co-admin 60 tion. The first four hours are exempt because the amount of an istration” refers to the administration of a single composition opioid administered intravenously immediately following containing both morphine and oxycodone, or pharmaceuti Surgery or trauma is not generally indicative of analgesia cally acceptable salts thereof, or to the administration of each required by the patient. During these initial hours the patient opioid agonist as a separate composition within a short is likely under the influence of the analgesia used during enough period of time such that the effective result is equiva 65 Surgery and/or would have little mobility that may not neces lent to that obtained when both Such opioid agonists are sitate the need for a heightened level of analgesia that is often administered as a single composition. required throughout later stages of recovery. US 8,012,990 B2 9 10 A factor of four is used in Equation 1 to convert the net TABLE 2 average hourly IV dosing ((m-n)/(h-4)) into a four-hour average since oral dosing of the morphine-oxycodone com Algorithm for the Conversion of Four-Hour Average bination will be about every four to six hours. Oral Morphine Equivalents to a First Dose of an Immediate Release The clinical bioequivalency factor considers the differ Morphine-Oxycodone Combination Administered Orally. ences in the bioavailability between IV and oral routes of opioid administration and the conversion of non-morphine Four-Hour Average Oral First Dose of opioid analgesics to a morphine equivalent dose. In certain Morphine Equivalent Dose Morphine-Oxycodone Combination embodiments, the clinical bioequivalency factor for various opioids may vary between about 1 and about 15. The range 10 0-10 mg 3 mg/2 mg also accounts for inter-patient variability, including the vari >10-s 15 mg 6 mg/4 mg ability between opioid naive and opioid tolerant patients. In >15-s20 mg 9 mg/6 mg Some embodiments, the clinical bioequivalency factor for >20-s30 mg 12 mg/8 mg various opioids may vary between about 1 and about 10. For 15 IV morphine, or a pharmaceutically acceptable salt thereof, According to the dosing algorithm of Table 2, if the four the clinical bioequivalency factor may vary between about 1 hour average oral morphine equivalent dose is between about and about 5. In certain embodiments, the clinical bioeduiva 0 mg and about 10 mg, the corresponding first dose of mor lency factor for morphine, or a pharmaceutically acceptable phine-oxycodone combination may be about 3 mg/2 mg; if salt thereof, may be about 2. In some embodiments, the clini the four-hour average oral morphine equivalent dose is cal bioeduivalency factor for oxycodone, or a pharmaceuti greater than about 10 mg and less than or equal to about 15 cally acceptable salt thereof, may be between about 1.5 and mg, the corresponding first dose of morphine-oxycodone 7.5. In other embodiments, the clinical bioequivalency factor combination may be about 6 mg/4 mg; if the four-hour aver for oxycodone, or a pharmaceutically acceptable Salt thereof, age oral morphine equivalent dose is greater than about 15 mg may be between about 3 and about 5. 25 and less than or equal to about 20 mg, the corresponding first The safety factor allows for a lesser amount of oral mor dose of morphine-oxycodone combination may be about 9 phine-oxycodone combination to be administered to mini mg/6 mg; if the four-hour average oral morphine equivalent mize the chance of overdosing or occurrence of adverse dose is greater than about 20 mg and less than or equal to events upon administration of the first dose. The safety factor 30 about 30 mg, the corresponding first dose of morphine-oxy may range from about 0.25 to about 1.0. In certain embodi codone combination may be about 12 mg/8 mg. ments, the safety factor may be about 0.50. In some embodi ments, the safety factor may be about 0.75. In some embodiments, when the four-hour average oral In certain embodiments, when the four-hour average oral morphine equivalent dose may be known or calculated as described above, the first dose of an immediate release mor morphine equivalent dose may be known or calculated as 35 described above, the first dose of an immediate release mor phine-oxycodone combination administered orally can be phine-oxycodone combination can be determined using the also determined using the dosing algorithm shown in Table 3. dosing algorithm shown in Table 1. TABLE 3 TABLE 1. 40 Algorithm for the Conversion of Four-Hour Average Oral Morphine Equivalent Dose to a First Dose of an Immediate Release Algorithm for the Conversion of Four-Hour Average Morphine-Oxycodone Combination Administered Orally. Oral Morphine Equivalents to a First Dose of an Immediate Release Morphine-Oxycodone Combination Administered Orally. Four-Hour Average Oral First Dose of Morphine Equivalent Dose Morphine-Oxycodone Combination Four-Hour Average Oral First Dose of 45 Morphine Equivalent Dose Morphine-Oxycodone Combination 0-30 mg 12 mg/8 mg >30-sq.0 mg 18 mg/12 mg 0-30 mg No greater than 12 mg/8 mg >40-s 120 mg 24 mg/16 mg >30-sq.0 mg 18 mg/12 mg >40-s 120 mg 24 mg/16 mg 50 According to the dosing algorithm of Table 3, if the four According to the dosing algorithm of Table 1, if the four hour average oral morphine equivalent dose is between about hour average oral morphine equivalent dose is between about 0 mg and about 30 mg, the corresponding first dose of mor 0 mg and about 30 mg, the corresponding first dose of mor phine-oxycodone combination may be about 12 mg/8 mg; if phine-oxycodone combination may be no greater than about the four-hour average oral morphine equivalent dose is 12 mg/8 mg; if the four-hour average oral morphine equiva 55 greater than about 30 mg and less than or equal to about 40 lent dose is greater than about 30 mg and less than or equal to mg, the corresponding first dose of morphine-oxycodone about 40 mg, the corresponding first dose of morphine-oxy combination may be about 18 mg/12 mg; if the four-hour codone combination may be about 18 mg/12 mg; if the four average oral morphine equivalent dose is greater than about hour average oral morphine equivalent dose is greater than 40 mg and less than or equal to about 120 mg. the correspond about 40 mg and less than or equal to about 120 mg, the 60 corresponding first dose of morphine-oxycodone combina ing first dose of morphine-oxycodone combination may be tion may be about 24 mg/16 mg. about 24 mg/16 mg. In some embodiments in which the four-hour average oral In certain embodiments, when the net average hourly intra morphine equivalent dose is between about 0 mg and about 30 venous dosing may be known or calculated as described mg, the first dose of an immediate release morphine-oxyc 65 above, the first dose of an immediate release morphine-oxy odone combination administered orally can be determined codone combination administered orally can be determined using the dosing algorithm shown in Table 2. using the dosing algorithm shown in Table 4. US 8,012,990 B2 11 12 TABLE 4 TABLE 6 Algorithm for the Conversion of Net Average Hourly Intravenous Algorithm for the Conversion of Net Average Hourly Intravenous Dosing to a First Dose of an Immediate Release Morphine-Oxycodone Combination Administered Orally. Dosing to a First Dose of an Immediate Release 5 Morphine-Oxycodone Combination Administered Orally. Net Average Hourly First Dose of Intravenous Dosing Morphine-Oxycodone Combination Net Average Hourly First Dose of 0-9 mg 12 mg/8 mg Intravenous Dosing Morphine-Oxycodone Combination >9-s 14 mg 18 mg/12 mg 10 >14 mg 24 mg/16 mg 0-9 mg No greater than 12 mg/8 mg >9-s14 mg 18 mg/12 mg According to the dosing algorithm of Table 6, if the net >14 mg 24 mg/16 mg average hourly intravenous dosing is between about 0 mg and about 9 mg, the corresponding first dose of morphine-oxyc 15 odone combination may be about 12 mg/8 mg; if the net According to the dosing algorithm of Table 4, if the net average hourly intravenous dosing is greater than about 9 mg average hourly intravenous dosing is between about 0 mg and and less than or equal to about 14 mg. the corresponding first about 9 mg, the corresponding first dose of morphine-oxyc dose of morphine-oxycodone combination may be about 18 odone combination may be no greater than about 12 mg/8 mg: mg/12 mg. If the net average hourly intravenous morphine if the net average hourly intravenous dosing is greater than administered is greater than about 14 mg. the corresponding about 9 mg and less than or equal to about 14 mg. the corre first dose of morphine-oxycodone combination may be about sponding first dose of morphine-oxycodone combination 24 mg of morphine and about 16 mg of oxycodone. may be about 18 mg/12 mg. If the net average hourly intra After the treatment regimen is converted, the morphine venous morphine administered is greater than about 14 mg. 25 oxycodone combination may be administered to the patients the corresponding first dose of morphine-oxycodone combi every 2 to 10 hours, or every 3 to 8 hours, or every 4 to 6 hours. nation may be about 24 mg of morphine and about 16 mg of Alternatively, the morphine-oxycodone combination may be oxycodone. administered at the discretion of the physician applying the In some embodiments in which the net average hourly method and prescribing the combination. For opioid tolerant intravenous dosing is between about 0 mg and about 9 mg, the 30 patients, the physician should take into consideration the first dose of an immediate release dose of a morphine-oxyc patient’s prior opioid dose and PCA dose of morphine and odone combination administered orally can be determined dose the Subject accordingly. using the dosing algorithm shown in Table 5. After the first oral immediate release dose of the morphine oxycodone combination, one or more Subsequent doses may 35 TABLE 5 be administered about every four to six hours apart. In certain embodiments, the one or more Subsequent doses may com Algorithm for the Conversion of Net Average Hourly Intravenous Dosing to a First Dose of an Immediate Release prise the same amount of morphine or a pharmaceutically Morphine-Oxycodone Combination Administered Orally. acceptable salt thereof and oxycodone or pharmaceutically 40 acceptable salt thereofas the first dose. In the event the patient Net Average Hourly First Dose of requires greater analgesia than what resulted from the first Intravenous Dosing Morphine-Oxycodone Combination dose of morphine and oxycodone, the one or more Subsequent O-3 mg 3 mg/2 mg doses can be increased compared to the first dose (up-titra >3-s5 mg 6 mg/4 mg >5-s7 mg 9 mg/6 mg tion). Thus, in certain embodiments, the Subsequent doses of >7-s9 mg 12 mg/8 mg 45 morphine-oxycodone combination may be co-administered about every four to six hours apart as follows: (i) if the first dose is about 3 mg of morphine, or a pharma According to the dosing algorithm of Table 5, if the net ceutically acceptable salt thereof, and about 2 mg of average hourly intravenous dosing is between about 0 mg and Oxycodone, or a pharmaceutically acceptable salt about 3 mg, the corresponding first dose of morphine-oxyc 50 thereof, then the first subsequent dose may be about 6 odone combination may be about 3 mg/2 mg; if the net aver mg of morphine, or a pharmaceutically acceptable salt age hourly intravenous dosing is greater than about 3 mg and thereof, and about 4 mg of oxycodone, or a pharmaceu less than or equal to about 5 mg, the corresponding first dose tically acceptable salt thereof; of morphine-oxycodone combination may be about 6 mg/4 (ii) if the first dose is about 6 mg of morphine, or a phar mg; if the net average hourly intravenous dosing is greater 55 maceutically acceptable salt thereof, and about 4 mg of than about 5 mg and less than or equal to about 7 mg, the Oxycodone, or a pharmaceutically acceptable salt corresponding first dose of morphine-oxycodone combina thereof, then the first subsequent dose may be about 9 tion may be about 9 mg/6 mg; if the net average hourly mg of morphine, or a pharmaceutically acceptable salt intravenous dosing is greater than about 7 mg and less than or thereof, and about 6 mg of oxycodone, or a pharmaceu equal to about 9 mg, the corresponding first dose of mor 60 tically acceptable salt thereof; (iii) if the first dose is about 9 mg of morphine, or a phar phine-oxycodone combination may be about 12 mg/8 mg. maceutically acceptable salt thereof, and about 6 mg of In some embodiments, when the net average hourly intra Oxycodone, or a pharmaceutically acceptable salt venous dosing is known or calculated as described above, the thereof, then the first subsequent dose may be about 12 first dose of an immediate release morphine-oxycodone com 65 mg of morphine, or a pharmaceutically acceptable salt bination administered orally can be determined using the thereof, and about 8 mg of oxycodone, or a pharmaceu dosing algorithm shown in Table 6. tically acceptable salt thereof; US 8,012,990 B2 13 14 (iv) if the first dose is about 12 mg of morphine, or a TABLE 7 pharmaceutically acceptable salt thereof, and about 8 mg of oxycodone, or a pharmaceutically acceptable salt Dosing Algorithm for Termination of an thereof, then the first subsequent dose may be about 18 Administration of Morphine-Oxycodone. mg of morphine, or a pharmaceutically acceptable salt 5 Current Combination thereof, and about 12 mg of oxycodone, or a pharma of Oral Morphine and ceutically acceptable salt thereof; and Oxycodone Dose Down-Titration (v) if the first dose is about 18 mg of morphine, or a About 3 mg 2 mg Can stop administration pharmaceutically acceptable salt thereof, and about 12 About 6 mg 4 mg Can stop administration mg of oxycodone, or a pharmaceutically acceptable salt 10 About 12 mg/8 mg Down-titrate to about 6 mg/4 mg for about 1-2 days, then stop administration thereof, then the first subsequent dose may be about 24 About 18 mg/12 mg Down-titrate to about 12 mg/8 mg for mg of morphine, or a pharmaceutically acceptable salt about 2 days, then to about 6 mg 4 mg for thereof, and about 16 mg of oxycodone, or a pharma about 1-2 days, then stop administration ceutically acceptable salt thereof. About 24 mg/16 mg Down-titrate to about 12 mg/8 mg for In the event that the patient requires lower doses than the 15 about 2 days, then to about 6 mg 4 mg for first administered oral immediate dose of morphine and oxy about 1-2 days, then stop administration codone to maintain analgesia or because of adverse effects, If a patient experiences any signs or symptoms of withdrawal, then the dose should be the one or more Subsequent doses may be decreased com increased to the prior dose and the down-titration should be tapered more slowly, pared to the first dose (down-titration). Thus, in some Morphine-Oxycodone Combination embodiments, Subsequent doses of morphine and oxycodone As described above, the morphine-oxycodone combina are co-administered about every four to six hours apart as tion may comprise morphine or a pharmaceutically accept follows: able salt thereof, and oxycodone or a pharmaceutically (i) if the first dose is about 24 mg of morphine, or a phar acceptable salt thereof. The salt may be selected from a group maceutically acceptable salt thereof, and about 16 mg of including, but not limited to, hydrochlorides, hydrobromides, oxycodone, or a pharmaceutically acceptable salt 25 thereof, then the first subsequent dose may be about 18 hydroiodides, Sulfates, bisulfates, nitrates, citrates, tartrates, mg of morphine, or a pharmaceutically acceptable salt bitartrates, phosphates, malates, maleates, napsylates, fuma thereof, and about 12 mg of oxycodone, or a pharma rates, succinates, acetates, terephthalates, pamoates and pec ceutically acceptable salt thereof; tinates. In some embodiments, the pharmaceutically accept (ii) if the first dose is about 18 mg of morphine, or a 30 able salt of morphine may be a hydrochloride, a sulfate or a pharmaceutically acceptable salt thereof, and about 12 tartrate salt, and the pharmaceutically acceptable salt of oxy mg of oxycodone, or a pharmaceutically acceptable salt codone may be a hydrochloride, a terephthalate or a pectinate thereof, then the first subsequent dose may be about 12 salt. In particular embodiments, the morphine-oxycodone mg of morphine, or a pharmaceutically acceptable salt combination comprises morphine Sulfate and oxycodone thereof, and about 8 mg of oxycodone, or a pharmaceu 35 hydrochloride. tically acceptable salt thereof; The morphine-oxycodone combination may comprise (iii) if the first dose is about 12 mg of morphine, or a morphine, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable salt thereof, and about 8 different pharmaceutical composition from oxycodone, or a mg of oxycodone, or a pharmaceutically acceptable salt pharmaceutically acceptable salt thereof. In particular thereof, then the first subsequent dose may be about 9 40 embodiments, morphine Sulfate and oxycodone hydrochlo mg of morphine, or a pharmaceutically acceptable salt ride are in the same pharmaceutical composition. thereof, and about 6 mg of oxycodone, or a pharmaceu A Suitable combination product of morphine and oxyc tically acceptable salt thereof; odone, or pharmaceutically acceptable salts thereof, is dis (iv) if the first dose is about 9 mg of morphine, or a phar closed in co-pending U.S. patent application Ser. Nos. maceutically acceptable salt thereof, and about 6 mg of 45 1 1/544,187, 12/469,438, and 12/567,209. oxycodone, or a pharmaceutically acceptable salt The pharmaceutical compositions for oral administration thereof, then the first subsequent dose may be about 6 may be administered in immediate release dosage forms. mg of morphine, or a pharmaceutically acceptable salt Immediate release dosage forms such as solid or liquid dos thereof, and about 4 mg of oxycodone, or a pharmaceu age forms include, by way of example and not limitation, tically acceptable salt thereof; and 50 tablets, troches, capsules, dispersions, Suspensions, solu (v) if the first dose is about 6 mg of morphine, or a phar tions, syrups, and the like. Pharmaceutical compositions may maceutically acceptable salt thereof, and about 4 mg of be presented as discrete units such as capsules, Sachets or oxycodone, or a pharmaceutically acceptable salt tablets, each containing a predetermined amount of each of thereof, then the first subsequent dose may be about 3 the morphine and oxycodone, orpharmaceutically acceptable mg of morphine, or a pharmaceutically acceptable salt 55 salts thereof, as a powder or granules or as a solution or a thereof, and about 2 mg of oxycodone, or a pharmaceu Suspension in an aqueous liquid, a non-aqueous liquid, an tically acceptable salt thereof. oil-in-water liquid emulsion ora water-in-oil liquid emulsion. Patients who no longer require analgesia may terminate the Such compositions may be prepared by any of the methods of administration of the medication. However, depending on the pharmacy but all methods include the step of bringing dose that is being administered, if a patient is taking the dose 60 together each of the opioids with a pharmaceutically accept on a regular basis (usually at least three to four times per day) able carrier. In general, the compositions may be prepared by for seven days, termination of the medication may lead to uniformly and intimately admixing the morphine and oxyc withdrawal and the symptoms may include anxiety, muscle odone, or pharmaceutically acceptable salts thereof, with liq aches, abdominal cramping, diarrhea, nausea and Vomiting. A uid carriers or finely divided solid carriers or both, and then, dosing algorithm to reduce or prevent withdrawal symptoms 65 if necessary, shaping the product into the desired presenta associated with termination of the morphine-oxycodone tion. As used herein the language “pharmaceutically accept combination may be found in Table 7. able carrier' is intended to include any and all solvents, dis US 8,012,990 B2 15 16 persion media, coatings, antibacterial and antifungal agents, thereof, may be released at a slower rate and over a longer isotonic and absorption delaying agents, and the like, com period of time. For example, in some embodiments, the con patible with pharmaceutical administration. The use of such trolled release formulation of morphine and oxycodone, or media and agents together with pharmaceutically active Sub pharmaceutically acceptable salts thereof, may release effec stances is well known in the art. These carriers include, by tive amounts of a mixture of morphine and oxycodone, or way of example and not limitation, Sugars, starches, cellulose pharmaceutically acceptable salts thereof, over 12 hours. In and its derivatives, malt, gelatin, talc, calcium sulfate, Veg other embodiments, the controlled release formulation may etable oils, synthetic oils, polyols, alginic acid, phosphate release effective amounts of morphine and oxycodone, or buffered solutions, emulsifiers, isotonic saline, and pyrogen pharmaceutically acceptable salts thereof, over 4 hours or free water. Supplementary active compounds can also be 10 incorporated into the compositions. over 8 hours. In still other embodiments, the controlled Oral compositions generally may include an inert diluent release formulation may release effective amounts of mor or an edible carrier. Suitable oral compositions may be, e.g., phine and oxycodone, or pharmaceutically acceptable salts enclosed in gelatin capsules or compressed into tablets, tro thereof, over 15, 18, 24 or 30 hours. ches, or capsules. For the purpose of oral therapeutic admin 15 In some embodiments of the invention, the dose of the istration, the active compound may be incorporated with morphine component, or a pharmaceutically acceptable salt excipients and used in the form of tablets, troches, or cap thereof, in the pharmaceutical compositions in accordance Sules. Pharmaceutically compatible binding agents, and/or with the present invention, or methods of the present inven adjuvant materials may be included as part of the composi tion, for opioid-naive human adults through oral administra tion. The tablets, pills, capsules, troches and the like may tion and in immediate release form may be about 3 mg or contain any of the following ingredients, or compounds of a more; about 6 mg or more; about 12 mg or more; about 18 mg similar nature: a binder Such as microcrystalline cellulose, or more; or about 24 mg or more, every four hours. For gum tragacanth or gelatin; an excipient such as starch or non-opioid-naive human adults through oral administration lactose, a disintegrating agent such as alginic acid, Primogel, in immediate release form, the dose of the morphine compo or corn starch; a lubricant such as magnesium Stearate or 25 nent may be higher. Sterotes; a glidant such as colloidal silicon dioxide; a Sweet ening agent Such as Sucrose or saccharin; or a flavoring agent In some embodiments of the invention, the analgesic dose Such as peppermint, methyl salicylate, or orange flavoring. of the oxycodone component, or a pharmaceutically accept It is especially advantageous to formulate oral composi able salt thereof, in the pharmaceutical compositions in tions in dosage unit form for ease of administration and uni 30 accordance with the present invention, or methods of the formity of dosage. The term “dosage unit form as used present invention, for opioid-naive human adults through oral herein refers to physically discrete units suited as unitary administration and in immediate release form may be 2 mg or dosages for the patient to be treated; each unit containing a more; 4 mg or more; 8 mg or more; 12 mg or more; or 16 mg predetermined quantity of active compound calculated to pro or more, every four hours. For non-opioid-naive human duce the desired therapeutic effect in association with the 35 adults through oral administration in immediate release form, required pharmaceutical carrier. The specification for the dos the dose of the oxycodone component may be higher. age unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active com The concentration of morphine and oxycodone in the blood pound and the particular therapeutic effect to be achieved, and stream will depend on the amount of compound administered the limitations inherent in the art of compounding Such an 40 in the composition as well as the route of administration and active compound for the treatment of individuals. the specific formulation used. For example, it is well known in The pharmaceutical compositions for oral administration the art that administration of morphine and oxycodone by IV may also be administered in controlled release dosage forms. injection typically results in a significant concentration of For example, controlled release dosage forms as described each compound in the blood stream almost immediately after hereinafter may be administered every 12- or 24-hours com 45 administration (without delay), whereas formulations prising, respectively, about 3 or 6 times the amount of the adapted for oral administration of morphine and oxycodone immediate-release dosage form. In this regard, it is well will typically achieve effective concentrations in the blood known that the change from immediate-release dosages to stream later than IV administration and at different concen controlled-release dosages of morphine and oxycodone, or trations depending on oral availability of the compounds. pharmaceutically acceptable salts thereof, may be a simple 50 Further, the routes of administration of the compounds may milligram to milligram conversion that results in the same further result in different inactivation and excretion rates of total “around-the-clock' dose of the morphine and oxyc morphine and oxycodone when administered in a combina odone, or pharmaceutically acceptable salts thereof. See tion. Therefore, it will be apparent to one of skill in the art that Cherny and Portenoy, “Practical Issues in the Management of the absolute and relative amounts of morphine and oxyc Cancer Pain in Textbook of Cancer Pain. Third Edition, Eds. 55 Wall and Meizack, Churchill Livingstone, 1994, 1453. odone, or pharmaceutically acceptable salts thereof, admin Controlled-release of the morphine and oxycodone, or istered to patients via oral administration to achieve efficacy pharmaceutically acceptable salts thereof, may be affected by with a lowerincidence of adverse side effects may differ from incorporating the morphine and oxycodone, or pharmaceuti the amounts of drugs required for IV administration or other cally acceptable salts thereof, into, by way of example and not 60 routes of administration. Table 8 provides pharmacokinetic limitation, hydrophobic polymers, including acrylic resins, data for healthy subjects that were orally co-administered a waxes, higher aliphatic alcohols, polylactic and polyglycolic single dose of morphine and oxycodone in dosage strengths acids and certain cellulose derivatives, such as hydroxypro of about 3 mg/2 mg and about 12 mg/8 mg. Values for the pylmethyl cellulose. In addition, the controlled release may observed maximum plasma concentration (C), total area be affected by using other polymer matrices, liposomes and/ 65 under the plasma concentration-time curve (AUC) and the or microspheres. The controlled release formulation of mor time to maximum plasma concentration (T,) were deter phine and oxycodone, or pharmaceutically acceptable salts mined. US 8,012,990 B2 17 18 TABLE 8 morphine dosing available for the calculation of the algo rithm. During the first four hours of that total time of IV PCA Pharmacokinetic Data for Oral Co-Administration of morphine dosing, the patient receives 9 mg of morphine. The Morphine and Oxycodone in a Ratio of about 3:2 by Weight. patient receives a total amount of 129 mg of morphine during Dose Cmax AUC ** Tmax the total time of IV PCA morphine administration. Therefore, Analyte (mg) (ng/mL) (ng himL/mg) (h) the net amount of morphine administered by IV PCA is cal Morphine 3 (n = 18) 3.9 4.24 O.SO culated by subtracting 9 mg (the amount of IV PCA morphine 12 (n = 18) 16.1 4.SS O.S4 administered during the first four hours of IV PCA) from the Oxycodone 2 (n = 18) 4.9 9.62 1.O total amount of 129 mg, thereby giving a net amount of 8 (n = 18) 17.8 9.62 1.O 10 morphine administered by IV PCA of 120 mg (129 mg-9 mg). *Pharmacokinetic analyses were performed using WinNonlin (RProfessional, Version 5.2. The net time of IV PCA morphine administration is calcu Standard noncompartmental analyses were conducted for computation of metrics of expo sure (CAUC), lated as the total time of 18 hours minus the first four hours, **Dose Adjusted. for a net time of IV PCA morphine administration of 14 hours (18 hours-4 hours). The net average hourly IV PCA morphine Plasma levels of morphine and oxycodone each appeared 15 administration is calculated by dividing the net amount of IV to increase linearly in a dose-proportionate manner after PCA morphine administration (120 mg) by the net time of IV single-dose administration of the morphine:oxycodone com PCA morphine administration (14 hours), which in this case bination (within the 3 mg/2 mg to 12 mg/8 mg dose range). All is 120 mg divided by 14 hours, which gives an net average dose-normalized, log-transformed parameters (C. and hourly IV morphine dosing of about 9 mg (120 mg/14 hours). AUCo.) were within the 80-125% bioequivalence criteria With reference to Table 4 above for a net average hourly IV limits, a demonstration of the dose proportionality between morphine dosing of about 9 mg per hour, the patient is con the 3 mg/2 mg and 12 mg/8 mg dose strengths. These data verted to a corresponding first oral dose of MOXDUOR) of 12 provide conclusive evidence of dose proportionality between mg of morphine Sulfate and 8 mg of oxycodone hydrochloride the two dosage strengths. in an immediate release dosage form. Method of Treating Patients 25 The present invention also relates to a method for the Example 2 treatment of pain in a human patient in need of analgesia by oral co-administration of an immediate release morphine A patient undergoes surgery that is completed at 2:00 PM, oxycodone combination in a weight ratio of about 3:2. In whereby IV PCA morphine is started at 2:30 PM. At 7:30AM Some embodiments such method includes the use of a dosing 30 the next morning IV PCA administration of morphine is algorithm to determine the first oral dose of the immediate stopped and the patient is converted to oral MOXDUOR, release morphine-oxycodone combination following admin which is a combination of morphine sulfate and oxycodone istration of IV opioid (e.g., morphine or a pharmaceutically hydrochloride in the ratio of approximately 3:2 by weight in acceptable salt thereof) to the patient. The dosing algorithm a form for immediate release. Therefore, from the beginning used in these methods may be a dosing algorithm described 35 of the IV PCA morphine administration to the end is a total above. time of 17 hours of IV PCA morphine dosing available for the For example, if the net average hourly intravenous dosing calculation of the algorithm. During the first four hours of that may be known or calculated, a dosing algorithm may be total time of IV PCA morphine dosing, the patient receives 9 applied such that if the netaverage hourly intravenous dosing mg of morphine IV PCA and a nurse gives 2 mg IV morphine is between about 0 mgandabout 9 mg, the corresponding first 40 through the PCA pump for a total of 11 mg of IV morphine dose of morphine-oxycodone combination may be about 12 during the first four hours. The patient receives a total amount mg/8 mg; if the net average hourly intravenous dosing is of 60 mg of morphine during the total time of IV PCA mor greater than about 9 mg and less than or equal to about 14 mg. phine administration. Therefore, the net amount of morphine the corresponding first dose of morphine-oxycodone combi administered by IV PCA is calculated by subtracting from the nation may be about 18 mg/12 mg. If the net average hourly 45 total amount of 60 mg the amount of IV PCA morphine intravenous morphine administered is greater than about 14 administered during the first four hours of IV PCA, which is mg, the corresponding first dose of morphine-oxycodone 11 mg, thereby giving a netamount of morphine administered combination may be about 24 mg of morphine and about 16 IV PCA of 49 mg (60 mg-11 mg). The net time of IV PCA mg of oxycodone. morphine administration is calculated as the total time of 17 The present invention will be understood more readily by 50 hours minus the first four hours, for a net time of IV PCA reference to the following examples, which are provided by morphine administration of 13 hours (17 hours-4 hours). The way of illustration and are not intended to be limiting of the net average hourly IV PCA morphine administration is cal invention. culated by dividing the net amount of IV PCA morphine administration (49 mg) by the net time of IV PCA morphine EXAMPLES 55 administration (11 hours), which in this case gives an net average hourly intravenous morphine dosing of about 4.5 mg Example 1 (49 mg/11 hours). With reference to Table 6 above for a net average hourly intravenous morphine dosing of about 4.5 mg. A patient undergoes surgery that is completed at 12:30 PM, the patient is therefore converted to a first dose of oral whereby IV PCA morphine is started at 1:00 PM. At 7:00AM 60 MOXDUOR at a dose of 12 mg of morphine sulfate and 8 mg the next morning IV PCA administration of morphine is of oxycodone hydrochloride in immediate release form. stopped and the patient is converted to oral MOXDUOR, which is a combination of morphine Sulfate and oxycodone Example 3 hydrochloride in the ratio of approximately 3:2 by weight in a form for oral administration for immediate release. There 65 An open-label, multicenter, multiple-dose pilot study of fore, from the beginning of the IV PCA morphine adminis flexible doses of oral MOXDUOR in a 3:2 ratio of morphine tration to the end is a total time of 18 hours of IV PCA sulfate to oxycodone hydrochloride, compared to PERCO US 8,012,990 B2 19 20 CET(R) (1-2 tablets of 5 mg/325 mg oxycodone/acetami TABLE 9-continued nophen) for the management of acute, moderate to severe postoperative pain following unilateral total knee arthro MOXDUO (R DOSes Administered to plasty or total hip arthroplasty was conducted. One objective Subjects Following IV PCA Morphine. of the study was to evaluate the adequacy of an algorithm for Calculate First Other conversion of IV PCA morphine to oral morphine-equivalent 4-h Ave First Subsequent Subsequent Final doses of MOXDUOR administered every 4 to 6 hours over a Oral ME Dose Dose Doses Dose 48-hour treatment period. Any adverse events, including Patient (mg/hr) (mg:mg) (mg:mg) (mg-mg) (mg-mg) Treatment-Emergent Adverse Events (TEAE) or Serious 6 4 12:8 No change No change 12:8 Adverse Events (SAE), including signs of abuse potential 10 7 26 12:8 No change 18:12 18:12 were also assessed. 8 11 12:8 18:12 12:8 12:8 9 3 12:8 No change No change 12:8 Testing Protocol 10 29 12:8 No change No change 12:8 Immediate post-operative analgesia consisted of PCA IV 11 24 12:8 18:12 24:16 NA? morphine. Subjects were connected to a PCA pump within 18:12 15 12 27 12:8 18:12 24:16 24:16 120 minutes after closure of surgery. Morphine doses (0.5-2.0 13 13 12:8 18:12 24:16 24:16 mg/dose) were administered by PCA pump with a 5-minute 18:12 lockout period and a maximum dose of 10 mg morphine per 12:8 hour. If the analgesia was insufficient, the one-hour limit may 18:12 be increased to ~15 mg morphine per hour at the discretion of 24:16 the doctor. During the course of IV PCA morphine, including 14 7 12:8 No change No change 12:8 prior to the initial dose of self-administered IV PCA mor ME = morphine equivalents phine, the nursing staff may administer via the PCA pump a 'subject inadvertently administered PERCOCET (R instead of MOXDUO (R) at 5 dose. single bolus dose of up to 5 mg of morphine, if necessary. The second dose (first subsequent dose) of MOXDUOR) Eligibility for enrollment of subjects in the study required received by the subjects (4-6 hours after the first dose) was the administration of an average oral morphine equivalent 25 more indicative of the amount of analgesia required as the dose of s 120 mg IV morphine by PCA pump (including Subjects became mobile and typically experienced more pain. morphine administered as a bolus by nursing staff and all Of the 14 subjects, 8 subjects did not require an upward dose self-administered morphine) over a period of at least 8 hours titration for the second dose. In fact, 1 of the 14 subjects (interval between first dose and final dose via pump). Follow down-titrated at the first subsequent dose and completed the ing Surgery, Subjects were disconnected from the PCA pump 30 study at the lower dose level. During the remainder of the between 5:00 AM-7:00AM on the morning following surgery 48-hour study period, 6 subjects required an increased dose to obtain an IV morphine baseline to be used with an algo and completed the study at the higher dose level compared to rithm to determine the starting dose for administration of oral the first administered dose. MOXDUOCR). Efficacy Results Calculation of total dose of morphine (mg) used during the 35 Both MOXDUOR and PERCOCETR) treatment groups total period of IV morphine PCA includes the sum of any had a similar proportion of responders (77% and 79%, respec morphine administered as a bolus by nursing staff and all tively). The efficacy endpoint of the SPIDs did not show a self-administered morphine. MOXDUOR study medication significant difference in values between MOXDUOR (mean was administered q. 4-6 h (not to exceed 6 doses in 24 hours) value of 148) and PERCOCETR) (mean value of 140); how and the last dose was administered 42 hours after the first 40 ever, the power to detect statistical significant differences dose. between treatments was low with these sample sizes. None The primary efficacy endpoint was the mean Sum of Pain theless, scores on individual domains of the Brief Pain Inven Intensity Difference scores during the 48-hour treatment tory-Short Form (BPI-SF) showed a significantly greater period (SPIDs). A subject who had at least 30% decrease in improvement of BPI-SF scores for MOXDUOR for pain pain intensity compared to baseline or had a good to excellent 45 interfering with general activity than the PERCOCETR) treat outcome on a global assessment of study medication scale at ment group at 48 hours/early termination. 24 or 48 hours was considered a responder. All adverse events Safety Results were described by onset, duration, resolution, relationship, The dosing algorithm for converting IV PCA morphine to and intensity (mild, moderate, severe). The algorithm for the first dose of oral MOXDUOR) was both conservative and conversion of IV morphine PCA to oral MOXDUOR) is 50 safe. None of the subjects administered MOXDUOR) discon shown above in Table 3. The doses administered to the sub tinued due to an adverse event, although one Subject in the jects throughout the study are provided below in Table 9. PERCOCET(R) treatment group discontinued because of a possibly related TEAE of stomach irritation. The overall inci TABLE 9 dence of nausea, pruritus, constipation, and dizziness was 55 higher during the IV PCA morphine use than during the same MOXDUO (R DOSes Administered to time period after first dose of study medication. Eleven (25%) Subjects Following IV PCA Morphine. subjects had moderate or severe nausea while on IV PCA Calculate First Other morphine. No moderate-severe vomiting, nausea, or diZZi 4-h Ave First Subsequent Subsequent Final ness was reported by subjects in the MOXDUOR) treatment Oral ME Dose Dose Doses Dose 60 group, although in the PERCOCETR) treatment group, mod Patient (mg/hr) (mg:mg) (mg:mg) (mg-mg) (mg:mg) erate to severe nausea and Vomiting were experienced by 4 1 21 12:8 18:12 18:12 18:12 (27%) and 3 (20%) of subjects, respectively. Ondansetron 2 21 12:8 18:12 24:16 18:12 was administered during the study treatment to 6 subjects in 18:12 3 9 12:8 6:4 6:4 6:4 both the MOXDUOR and PERCOCET.R treatment groups. 4 31 18:12 No change 24:16 24:16 65 “Woozy' was the only potential abuse liability symptom that 5 13 12:8 No change No change 12:8 was reported and occurred in one subject in the PERCO CET(R) treatment group. US 8,012,990 B2 21 22 Conclusion (iii) if the four-hour average oral morphine equivalent The analgesic efficacy of MOXDUOR and PERCOCETR dose is greater than about 40 mg and less than or equal treatment groups were similar in terms of proportion of to about 120 mg. then the first dose is about 24 mg of responders and median SPIDs. In addition, values for the morphine Sulfate and about 16 mg of oxycodone Sum of Pain Response and Pain Intensity Difference 5 hydrochloride. (SPRID), mean distance walked on Day 2 of rehabilitation, 2. The method of claim 1, wherein: and time to remedication were similar for both treatment (i) if the four-hour average oral morphine equivalent dose groups (data not shown). The MOXDUOR) dosing treatment is between about 0 mg and about 10 mg, then the first group had a significantly lower BPI-SF score for pain inter dose is about 3 mg of morphine Sulfate and about 2 mg fering with general activity than the PERCOCET(R) treatment 10 of oxycodone hydrochloride; group at 48 hours/early termination. For example, patients (ii) if the four-hour average oral morphine equivalent dose being administered MOXDUOR had a mean 96 improvement is greater than about 10 mg and less than or equal to in BPI from baseline to end of treatment for general activity, about 15 mg, then the first dose is about 6 mg of mor walking ability, and ability to sleep of 54%, 35%, and 31%, phine Sulfate and about 4 mg of oxycodone hydrochlo respectively. Patients that were administered PERCOCET(R) 15 ride; had BPI scores of 19%, 17%, and 15%, respectively, for the (iii) if the four-hour average oral morphine equivalent dose same categories. No related SAEs, severe TEAEs, or AEs is greater than about 15 mg and less than or equal to leading to discontinuation occurred in the MOXDUOR) treat about 20 mg, then the first dose is about 9 mg of mor ment group. In the PERCOCETR) treatment group, 1 subject phine Sulfate and about 6 mg of oxycodone hydrochlo had a severe TEAE of dry mouth, and 1 subject discontinued ride; due to an adverse event of stomachirritation. The incidence of (iv) if the four-hour average oral morphine equivalent dose moderate to severe nausea and Vomiting was higher in the is greater than about 20 mg and less than or equal to PERCOCET(R) treatment group compared with the equi-an about 30 mg. then the first dose is about 12 mg of algesic MOXDUOR dosing treatment group, which had no morphine Sulfate and about 8 mg of oxycodone hydro Such events. 25 chloride. The dosing algorithms of the instant invention allows for 3. The method of claim 1, wherein if the four-hour average the determination of a simple and convenient starting dose of oral morphine equivalent dose is between about 0 mg and MOXDUOR for patients being administered IV opioids, about 30 mg, then the first dose is about 12 mg of morphine such as morphine. The titration algorithms also allow for the sulfate and about 8 mg of oxycodone hydrochloride. ease of upward and downward titration of MOXDUOR, if 30 4. The method of claim 1, wherein morphine sulfate and required. The algorithms used in the present invention pro oxycodone hydrochloride are co-administered in a single vide surprising and unexpected results since patients being dosage form. administered MOXDUOR) reached a level of analgesia within 5. The method of claim 1, wherein the four-hour average the first administered dose, or the first subsequent dose of oral morphine equivalent dose is determined according to MOXDUOR. These results are in contrast to patients that 35 equation 1: may require up to 48-hours of dose titrations to obtain anal gesia. See S. Mercadante, Eur: J. Pain 11 (2007) 823-30 (“In conclusion dose titration with oral opioids, particularly with 4-Hour Average (1) short-onset drugs such as morphine, may provide adequate Oral Morphine = (Ah - 4 X 4) XbXS pain relief in about 48 hr in most patients'). 40 Equivalent Dose It should be understood, of course, that the foregoing relates only to certain disclosed embodiments of the present invention and that numerous modifications or alterations may wherein m is the amount (mg) of the opioid administered be made therein without departing from the spirit and scope of intravenously, n is the amount (mg) of opioid administered the invention as set forth in the appended claims. 45 during the first four hours of intravenous administration, his the total hours of opioid intravenous administration, b is a What is claimed is: clinical bioeduivalency factor, and S is a safety factor. 1. A method of converting a treatment for pain comprising 6. The method of claim 5, wherein the clinical bioequiva intravenous administration of an opioid to a treatment for pain lency factor is about 2. comprising oral co-administration of immediate release mor 50 7. The method of claim 5, wherein the safety factor is about phine Sulfate and oxycodone hydrochloride in a weight ratio O.75. of about 3:2, in human patients in need of analgesia, the 8. The method of claim 1, comprising orally co-adminis method comprising: tering one or more Subsequent doses of morphine Sulfate and determining a four-hour average oral morphine equivalent oxycodone hydrochloride about every four to six hours, dose of the opioid administered intravenously; and 55 wherein the one or more Subsequent doses comprises the orally co-administering a first dose of an immediate release same amount of morphine Sulfate and oxycodone hydrochlo dosage form of morphine Sulfate and oxycodone hydro ride as the first dose. chloride, wherein: 9. The method of claim 1, comprising orally co-adminis (i) if the four-hour average oral morphine equivalent tering one or more Subsequent doses of morphine Sulfate and dose is between about 0 mg and about 30 mg. then the 60 oxycodone hydrochloride about every four to six hours, first dose is no greater than about 12 mg of morphine wherein: sulfate and about 8 mg of oxycodone hydrochloride: (i) if the first dose is about 12 mg of morphine sulfate and (ii) if the four-hour average oral morphine equivalent about 8 mg of oxycodone hydrochloride, then the first dose is greater than about 30 mg and less than or equal Subsequent dose is about 18 mg of morphine Sulfate and to about 40 mg. then the first dose is about 18 mg of 65 about 12 mg of oxycodone hydrochloride; morphine Sulfate and about 12 mg of oxycodone (ii) if the first dose is about 18 mg of morphine sulfate and hydrochloride: about 12 mg of oxycodone hydrochloride, then the first US 8,012,990 B2 23 24 Subsequent dose is about 24 mg of morphine Sulfate and (ii) if the first dose is about 18 mg of morphine sulfate and about 16 mg of oxycodone hydrochloride. about 12 mg of oxycodone hydrochloride, then the first 10. The method of claim 2, comprising orally co-adminis Subsequent dose is about 12 mg of morphine Sulfate and tering one or more Subsequent doses of morphine Sulfate and about 8 mg of oxycodone hydrochloride; oxycodone hydrochloride about every four to six hours, 5 (iii) if the first dose is about 12 mg of morphine sulfate and wherein: about 8 mg of oxycodone hydrochloride, then the first (i) if the first dose is about 3 mg of morphine sulfate and Subsequent dose is about 9 mg of morphine Sulfate and about 2 mg of oxycodone hydrochloride, then the first about 6 mg of oxycodone hydrochloride. Subsequent dose is about 6 mg of morphine Sulfate and 12. The method of claim 2, comprising orally co-adminis about 4 mg of oxycodone hydrochloride; 10 tering one or more Subsequent doses of morphine Sulfate and (ii) if the first dose is about 6 mg of morphine sulfate and oxycodone hydrochloride about every four to six hours, about 4 mg of oxycodone hydrochloride, then the first wherein: Subsequent dose is about 9 mg of morphine Sulfate and (i) if the first dose is about 24 mg of morphine sulfate and about 6 mg of oxycodone hydrochloride; about 16 mg of oxycodone hydrochloride, then the first (iii) if the first dose is about 9 mg of morphine sulfate and 15 Subsequent dose is about 18 mg of morphine Sulfate and about 6 mg of oxycodone hydrochloride, then the first about 12 mg of oxycodone hydrochloride; Subsequent dose is about 12 mg of morphine Sulfate and (ii) if the first dose is about 18 mg of morphine sulfate and about 8 mg of oxycodone hydrochloride; about 12 mg of oxycodone hydrochloride, then the first (iv) if the first dose is about 12 mg of morphine sulfate and Subsequent dose is about 12 mg of morphine Sulfate and about 8 mg of oxycodone hydrochloride, then the first about 8 mg of oxycodone hydrochloride; Subsequent dose is about 18 mg of morphine Sulfate and (iii) if the first dose is about 12 mg of morphine sulfate and about 12 mg of oxycodone hydrochloride; about 8 mg of oxycodone hydrochloride, then the first (v) if the first dose is about 18 mg of morphine sulfate and Subsequent dose is about 9 mg of morphine Sulfate and about 12 mg of oxycodone hydrochloride, then the first about 6 mg of oxycodone hydrochloride; Subsequent dose is about 24 mg of morphine Sulfate and 25 (iv) if the first dose is about 9 mg of morphine sulfate and about 16 mg of oxycodone hydrochloride. about 6 mg of oxycodone hydrochloride, then the first 11. The method of claim 1, comprising orally co-adminis Subsequent dose is about 6 mg of morphine Sulfate and tering one or more Subsequent doses of morphine Sulfate and about 4 mg of oxycodone hydrochloride; oxycodone hydrochloride about every four to six hours, (v) if the first dose is about 6 mg of morphine sulfate and wherein: 30 about 4 mg of oxycodone hydrochloride, then the first if the first dose is about 24 mg of morphine sulfate and Subsequent dose is about 3 mg of morphine Sulfate and about 16 mg of oxycodone hydrochloride, then the first about 2 mg of oxycodone hydrochloride. Subsequent dose is about 18 mg of morphine Sulfate and about 12 mg of oxycodone hydrochloride; k k k k k