USOO8163.731B2

(12) United States Patent (10) Patent No.: US 8,163,731 B2 Slater et al. (45) Date of Patent: Apr. 24, 2012

(54) METHOD AND DOSAGE REGIMENS FOR OTHER PUBLICATIONS ELMINATING ACHEMICAL SUBSTANCE IN Abramowitz, M.(Editor). : An Alternative to Metha BLOOD done. The Medical Letter, (2003), 13-15, vol. 45, (Issue W1150A)Feb. 17. (75) Inventors: Kenneth C. Slater, Manchester, MA AZar, M.R. et al. A Non-invasive gating device for continuous drug (US); Brenda E. Richardson, delivery that allows control over the timing and duration of sponta neous withdrawal. J.Neurosci. Methods,(May 30, 2004), 129 Manchester, MA (US); Scott M. 35, vol. 135 (1-2). Connors, Methuen, MA (US); Wei-wei Barnett, P.G. et al. Research Report. A Meta-Analysis Comparing Chang, Boston, MA (US) Buprenorphine to for Treatment of Opiate Dependence. Addiction(2001),683-690, vol. 96. (73) Assignee: Rhodes Technologies, Coventry, RI Barnett, P.G. et al. The Cost-effectiveness of buprenorphine mainte (US) nance therapy for opiate addiction in the United States. Addic tion(2001), 1267-1278,V96. (*) Notice: Subject to any disclaimer, the term of this (Continued) patent is extended or adjusted under 35 U.S.C. 154(b) by 477 days. Primary Examiner — Brandon Fetterolf Assistant Examiner — Kathrien Cruz (21) Appl. No.: 12/195,143 (74) Attorney, Agent, or Firm — Brinks Hofer Gilson & Lione (22) Filed: Aug. 20, 2008 (57) ABSTRACT (65) Prior Publication Data A method of reducing the concentration of a chemical or drug US 201O/OO48535A1 Feb. 25, 2010 Substance in the blood plasma that targets the same or similar receptors as the normal neurotransmitters in the central or (51) Int. Cl. peripheral nervous system includes titrating an initial peak A6 IK3I/485 (2006.01) concentration of the chemical or drug Substance in the blood A6 IK3I/554 (2006.01) for a predefined dosing period, titrating a lowest concentra A63/479 (2006.01) tion level of the chemical or drug substance in the blood (52) U.S. Cl...... 514/211.13: 514/282: 514/305 immediately before the end of the dosing period, and provid (58) Field of Classification Search ...... 514/211.13, ing a plurality of Subsequent dosing periods where each Sub 514/282,305 sequent dosing period requires administration of a dosing See application file for complete search history. amount of the chemical or drug Substance and titrating of the peak concentration and the lowest concentration level to (56) References Cited ensure that the lowest concentration level of the chemical or drug Substance in the blood plasma for the Subsequent dosing U.S. PATENT DOCUMENTS period is decreased by not more than five percent of the lowest 6,277.384 B1* 8/2001 Kaiko et al...... 424/400 concentration level of the previous dosing period and where 7,172,767 B2 2/2007 Kaiko et al. the plurality of dosing periods added together extends the method for seventy days or more. FOREIGN PATENT DOCUMENTS CA 2621575 A1 8/2008 12 Claims, 4 Drawing Sheets

16 14 V

12 d E O g 8 2. 6 ?

40 SO 60 70 80

Days in Treatment US 8,163,731 B2 Page 2

OTHER PUBLICATIONS Strain, E.C. etal. Buprenorphine Versus Methadone in the Treatment of Dependence: Self Reports, Urinanalysis, and Addiction Becker, A.B. et al. Gradual Dose Taper Following Chronic Severity Index. Journal of Clinical Psychopharmacology. (Feb. 1996) Buprenorphine. American Journal of Addictions. (2001), 111 58-67 vol. 16 No. 1. 121, vol. 10. Strang, Jand Gossop, M. Comparison of Linear versus Inverse Expo Bickel, W.K. et al. Buprenorphine dosing every 1.2 or 3 Days in opioid-dependent patients. Psychopharmacology (1999) 111-11, vol. nential Methadone Reduction Curves in the Detoxification of Opiate 146. Addicts. Addictive Behavior. (1990), 541-547, vol. 15. Breen, C.L. et al. Cessation of methadone maintenance treatment Camarasa, X. et al. -assisted rapid methadone discontinu using buprenorphine:transfer from methadone to buprenorphine and ation: A Pilot Study, European Addition Research, 2007, vol. 13, pp. Subsequent buprenorphine reductions. Drug and Alcohol Depen 20-24. dence (2003),49-55, vol. 71. Strain, E. C. etal. Relative bioavailability of different buprenorphine Calsyn, D.A. etal. Slow Tapering From Methadone Maintenance in a formulations under chronic dosing conditions, Drub and Alcohol Program Encouraging Indefinite Maintenance. Journal of Substance Dependence, 2004, vol. 74, pp. 37-43, Elsevier. Abuse Treatment (2006), 159-163, vol. 30. Gilson, A.M., et al., A Reassessment of Trends in the Medical use and Caplehorn, J. Comments on Matticket al:The Need for Independent Abuse of Opioid and Implications for Diversion Control: Data Reanalyses. Addiction (2000) 1633-1634, vol. 98. 1997-2002, Journal of and Symptom Management, 2004, vol. Chawarski, M.C. etal. Buprenorphine Tablet Versus Liquid: A Clini 28, No. 2. cal Trial comparing Plasma Levels, Efficacy, and Symptoms.Journal Miller, N. S. and Greenfield, A., Patient Characteristics and Risks of Substance Abuse Treatment.(2005),307-312. Factors for Development of Dependence on and Fiellin, D.A & O'Connor, P.G. New Federal Initiatives to Enhance , American Journal of Therapeutics, 2004, vol. 11, pp. the Medical Treatment of Opioid Dependence. Annals of Internal 26-32. Medicine(2002),688-692, vol. 137. Application for Inclusion of Buprenorphine in the WHO Model List Fiellin, D.A. et al. Counseling Plus Buprenorphine- of Essential Medicines, WHO: Department of Mental Health and Mainetenance Therapy for Opioid Dependence. The New England Substance Abuse, 2004, 1-49. Journal of Medicine(2006).365-374, vol. 355. ACT Methadone Treatment Guidelines, ACT Health, 2003, 1-102. Law, F.D. et al. The Clinical use of Buprenorphine in Opiate Bickel, Warren K. et al., “Buprenorphine Treatment of Opioid Addiction: Evidence and Practice. Acta Neuropsychiatrica, Dependence: A Review.” Experimental and Clinical (2004).246-274, vol. 16. Litten.R.Z. & Allen, J.P. Medications for Alcohol, Illicit Drug, and Psychopharmacology, 1995, pp. 477-489, 3(4), American Psycho Tobacco Dependence. An Update of Research Findings. Journal of logical Association, Inc., US. Substance Abuse Treatment (1999) 105-112 vol. 16.No. 2. Bickel, Warren K. et al., “Effects of Adding Behavioral Treatment to Mahowald, M.L. Opioid use by Patients in an Orthopedics Spine Opioid Detoxification with Buprenorphine.” Journal of Consulting Clinic. Arthritis and Rheumatism (2005).312-321, vol. 52. and Clinical Psychology, 1997, pp. 803-810, 65(5), American Psy Marsch, L.A. et al. Comparison of Pharmacological Treatments for chological Association, Inc., US. Opioid-Dependent Adolescents: A Randomized Controlled Trial. Johnson, Rolley E. et al., “Buprenorphine: how to use it right.” Drug Archives of General Psychiatry.(2005), 1157-116 vol. 62. and Alcohol Dependence, 2003, pp. S59-S77, 70, Elsevier Science Mattick, R.P. et al. Buprenorphine versus Methadone Maintenance Ireland, Ltd. Theralpy: A Randomized Double-Blind Trial With 405 Opioid Kuhlman, James J., Jr. et al., “Relationship of plasma buprenorphine Dependent Patients. Addiction(2003),441-452, vol. 98. and to withdrawal symptoms during dose induc O'Connor, P.G. Methods of Detoxification and Their Role in Treating tion, maintenance and withdrawal from Sublingual buprenorphine.” Patients with Opioid Dependence.JAMA (2005),961-963, vol. 294. Addiction, 1998, pp. 549-559, 93 (4), Society for the Study of Addic O'Connor, P.G. et al. Three Methods of Opioid Detoxification in a tion to Alcohol and Other Drugs, Carfax Publishing Limited. Primary Care Setting. Ann Inter.Med. (1997), 526-530 vol. 127. Wolff, Kim et al., “Methadone Concentrations in Plasma and Their Phillips, G.T. & Bradley, B. The Influence of Psychological Factors Relationship to Drug Dosage.” Clinical Chemistry, 1991, pp. 205 on the Opiate Withdrawal Syndrome. British Journal of Psychia 209, 37(2). try(1986), 235-238, vol. 149. European Search Report, European Application No. EP 09 168344. Raisch, D.W. et al. Opioid Dependence Treatment, Including Johnson, Rolley E. et al., Buprenorphine: how to use it right, Drug Buprenorphine/Naloxone. AnnPharmacother (2002) 312-321 vol. and Alcohol Dependence, 70 (2003), pp. S59-S77. 36. Becker, Ami B. et al., Gradual Dose Taper Following Chronic Raistrick, D.et al. A Comparison of Buprenorphine and Lofexidine Buprenorphine, the American Journal on Addiction, 10 (2001), pp. for Community Opiate Detoxification: Results From a Randomized 111-121. Controlled Trial. Addiction 92005) 1860-1862 vol. 100. Amass, Leslie et al., A Preliminary Investigation of Outcome Fol Rosenblatt A.B. & Nagy A.M. Management of Pain in Addicted lowing Gradual or Rapid Bupronerphine Detoxification, Journal of Illicit and Legal Substance Abusing Patients.Pain Practice.(2005), Addictive Diseases, vol. 13, No. 3, 1994, pp. 33-45. 2-10, vol. 5.No. 1. Bickel, Warren K. et al., Effects of Adding Behavioral Treatment to Schottenfeld, R.S. et al. Thrice Weekly Versus Daily Buprenorphine Opioid Detoxification With Buprenorphine, Journal of Consulting Maintenance. Biol. Psychiatry (2000), 1072-1079, vol. 47. and Clinical Psychology, American Psychological Association, vol. Simpson, D.D. etal. Drug Abuse Treatment Process Components that 65, No. 5, 1997, pp. 803-810. Improve Retention. Journal of Substance Abuse Treatment. (1997),565-572, vol. 14 No. 6. * cited by examiner U.S. Patent Apr. 24, 2012 Sheet 1 of 4 US 8,163,731 B2

sS3s& S.

S

S

VO S N O OO t v y 6u u esop AleO U.S. Patent Apr. 24, 2012 Sheet 2 of 4 US 8,163,731 B2

d N w

v w va

CO O ra

n O H

Vo On o in C r- cy S. d. st oxo

od N

N N

d d

(eleos fo) fu u esop AlleO U.S. Patent Apr. 24, 2012 Sheet 3 of 4 US 8,163,731 B2

|

(eleos 6o) (u/6u) uope JueouOO U.S. Patent Apr. 24, 2012 Sheet 4 of 4 US 8,163,731 B2

9 E OO CN asDa as C. C. O O CN ON v O

C O r g O) O O ?

O O y S. C T O O y O O v (eleos fol) (u/6u) uOle JueouOO US 8,163,731 B2 1. 2 METHOD AND DOSAGE REGIMIENS FOR inhibitors such as bupropion; tricyclic antidepressants— ELMINATING ACHEMICAL SUBSTANCE IN TCAS-Such as , , , tra BLOOD Zodone, and ; monoamine oxidase inhibitors— MAOIs—such as phenelzine, moclobenmide; buspirone); BACKGROUND OF THE INVENTION methylxanthines such as caffeine, theophylline, and theobro mine; nicotine; methylphenidate; and other drugs that act on 1. Field of the Invention the nervous systems either central or peripheral, or both. The present invention relates generally to chemical or drug Other chemical or drug Substances that do not primarily act on Substances in the blood as they relate to physical dependence. the central nervous system can also cause withdrawal, includ The present invention relates to a method and dosages for 10 ing antihypertensives in particular beta blockers, and glucos controlling the elimination of a chemical or drug Substance in teroids. blood in order to eliminate physical dependence to these and For many of these chemicals and drug Substances, the related chemicals or drug Substances. central nervous system effects are more noticeable. They act 2. Description of the Prior Art by preventing the uptake of the normal neurotransmitters There are numerous legal and illegal chemical or drug 15 Such as dopamine, serotonin and norepinephrine, and estab Substances currently available in the marketplace. Certain lish new pathways for neurotransmission and cellular func types of chemical or drug Substances that are taken repeatedly tion. The peripheral nervous system, however, is also cause the body to develop a physical dependence for the affected, involving disparate parts of the body such as the chemical or drug Substance. This physical dependence for heart or gastrointestinal system. Some of chemicals and drug Substances is called an addiction. Following repeated exposure on a prolonged basis, the Discontinuation of the substance by an individual who has body systems develop physical dependence by adapting to the developed a physical dependence for the chemical or drug uptake of the administered chemical or drug Substances as Substance typically causes untoward withdrawal symptoms in they seek new conditions of homeostasis. When abrupt the individual. change to the new homeostasis occurs, unpleasant and some Examples of chemical or drug Substances that can lead to 25 times life threatening withdrawal symptoms accompany physical dependence include alcohol, (, rapid cessation in dosing. Withdrawal symptoms may include , , , hydrocodone, oxyc dizziness, light-headedness, Vertigo or feeling faint, shock odone, , , diacetylmorphine or like sensations or paresthesia, anxiety, diarrhea, fatigue, , , dipropanoylmorphine, benzylmor instability, headache, insomnia, irritability, nausea or vomit phine, , , , methadone, tra 30 ing, palpitations, tremor, and visual disturbances. Craving in madol, propxyphene), amphetamines and derivatives such as the case of addictive chemical or drug Substances can occur MDMA (3.4-Methylenedioxy-N-methamphetamine) and either earlier or later following cessation of intake. More methamphetamine, barbiturates (allobarbital, amobarbital, serious withdrawal effects may include convulsions, halluci aprobarbital, alphenal, barbital, brallobarbital, Phenobar nations, catatonia, coma, Suicidal tendencies, hyperthermia, bital), benzodiazepines both hypnotic (estazolam, flu 35 violence, and psychosis. Fatality may occur under certain razepam, midazolam, triazolam, temazepam, nimetazepam, situations such as mediated by cardiac arrest. brotizolam, flunitrazepam, loprazolam, lormetazepam, and To be more precise, neurotransmitters are various chemical nitrazepam), and anxiolytic (alprazolam, chlordiazepoxide, Substances that include monoamines (dopamine, epineph clonazepam, cloraZepate, diazepam, lorazepam, oxazepam, rine, norepinephrine, serotonin, and melatonin), amino acids prazepam, and bromazepam), gamma-hydroxybutyric acid, 40 (glutamic acid, gamma aminobutyric acid, aspartic acid and methaqualone, cocaine, anticonvulsants (acetazolamide, car glycine), peptides (vasopressin, Somatostatin, etc.), and oth bamazepine, clobazam, clonazepam, diazepam, divalproex erS Such as adenosine, histamine, etc., that through binding to Sodium, ethoSuximide, ethotoin, felbamate, fosphenytoin, receptors mediate neurotransmission. When chemical or drug gabapentin, lamotrigine, levetiracetam, mephenytoin, meth Substances that cause physical dependence competitively arbital, methSuximide, methazolamide, oxycarbazepine, 45 bind to specific receptors, accumulation of specific neu Phenobarbital, phenytoin, phensuXimide, pregabalin, primi rotransmitters can occur. For instance, dopamine levels can done, Valproic acid, Stiripentol, tiagabine, topiramate, tri increase in the nucleus accumbens, and cause the methadione, vigabatrin, and Zonisamide); mood stabilizers associated with opiate use. The usual doses of chemical or (lithium salts, valproic acid, divalproex sodium, Sodium val drug Substances may saturate the receptors. After extended proate, lamotrigine, carbamazepine, gabapentin, oXcarba 50 periods of repeated dosing, a Sudden withdrawal of the Zepine, and topiramate), antipsychotics (first generation— chemical or drug Substance can deplete the neurotransmitters butyrophenones Such as haloperidol, phenothiazines such as that had been released, and precipitate the withdrawal symp chlorpromazine, fluiphenazine, perphenazine, thioridazine, tOmS. trifluoperazine, mesoridazine, promethazine, triflupro Traditional methods for treatment of dependence involve mazine, and levomepromazine, thioxanthenes Such as chlor 55 either very rapid tapering of the drug Substance, e.g. nicotine prothixine, thiothixene, flupenthixol, and Zuclopenthixol); transdermal patches (Habitrol) for Smoking cessation or second generation—clozapine, olanzapine, risperidone, que through replacement therapy, e.g. methadone and buprenor tiapine, Ziprasidone, amisulpride, paliperidone, and deriva phine (SuboxoneR/Subutex(R), at sustained relatively high tives; third generation—aripiprazole; and others such as tet doses. rabenazine and cannabinoids; antidepressants (serotonin 60 Conventional therapies for opioid addiction treatment are norepinephrine reuptake inhibitors—SSRIs include replacement therapies using other opioid agonists. Metha fluoxetine, paroxetine, escitalopram, citalopram, and Sertra done and buprenorphine replacement therapies are typically line; serotonin-norepinephrine reuptake inhibitors—SN aimed at maintenance therapy, not at total cessation. As an RIs—include Venlafaxine and dulloxetine; noradrenergic and example, patients in maintenance treatment with methadone specific serotonergic antidepressinats—NASSAS-Such as 65 should be titrated to a dose at which opioid symptoms are ; norepinephrine reuptake inhibitors—NRIs— prevented for 24 hours, drug hunger or craving is reduced, the Such as reboxetine; norepinephrine-dopamine reuptake euphoric effects of self-administered opioids are blocked or US 8,163,731 B2 3 4 attenuated, and the patient is tolerant to the sedative effects of cian may continue decreasing the dose but at a more gradual methadone. Most commonly, clinical stability is achieved at rate. Likewise for sertraline hydrochloride, the instructions doses between 80 to 120 mg/day. state a gradual reduction in the dose rather than abrupt ces In the case of buprenorphine, the goal is to achieve an sation is recommended whenever possible. If intolerable optimal maintenance dose. The steps include adjusting the 5 symptoms occur following a decrease in the dose or upon dose until the maintenance dose is achieved. The recom discontinuation of treatment, then resuming the previously mended target dose of SuboxoneR) is 16 mg/day. Clinical prescribed dose may be considered. Subsequently, the physi studies have shown that 16 mg of SubuteXCR) or Suboxone(R) is cian may continue decreasing the dose but at a more gradual a clinically effective dose compared with placebo and indi rate. cate that doses as low as 12 mg/day may be effective in some 10 For amphetamines, there is no current stated practice of patients. The dosage of Suboxone(R) should be progressively dealing with physical dependence. adjusted in increments/decrements of 2 mg or 4 mg to a level that holds the patient in treatment and Suppresses opioid Forbenzodiazepines Such as ChloraZepate, the instructions withdrawal effects. This is likely to be in the range of 4 mg to state that after extended therapy, abrupt discontinuation of 24 mg per day depending on the individual. 15 CloraZepate should generally be avoided and a gradual dos Although it has been recognized by many that one way to age tapering schedule followed. prevent withdrawal symptoms is through tapering the patient For methadone, the official prescribing information states off the medication that led to the physical dependence in the that there is considerable variability in the appropriate rate of first place, the practice is variable and usually deficient. methadone taper in patients choosing medically Supervised Examples of inadequacies in the current state of practice of withdrawal from methadone treatment. It is generally Sug tapering will now be described. gested that dose reductions should be less than 10% of the Treatment for alcohol withdrawal is not based on the taper established tolerance or maintenance dose, and that 10 to ing concept at all, but is designed to treat the side effects 14-day intervals should elapse between dose reductions. The which can be fatal. For instance, benzodiazapines are the first information further states that patients should be apprised of line treatment for delirium tremens, with addition of phe 25 the high risk of relapse to illicit drug use associated with mobarbital or propofol should the former not be effective. discontinuation of methadone maintenance treatment. A Survey on the actual practice of tapering shows that the For buprenorphine, the official prescribing information instructions are either absent or vague or that tapering is done states the following regarding reducing dosage and stopping in Such large decrements that they cause Sudden blood level treatment: The decision to discontinue therapy with Subox changes. 30 one(R) or SubuteXR) after a period of maintenance or brief For serotonin and norepinephrine reuptake inhibitors such stabilization should be made as part of a comprehensive treat as venaflexane, a gradual reduction in the dose rather than ment plan. Both gradual and abrupt discontinuations have abrupt cessation is recommended whenever possible. If intol been used, but no controlled trials have been undertaken to erable symptoms occur following a decrease in the dose or determine the best method of dose taper at the end of treat upon discontinuation of treatment, then the recommendation 35 ment. is to resume the previously prescribed dose. In fact, the For fentanyl, the official prescribing information states the instructions state that symptoms associated with discontinu following for the discontinuation of DURAGESICR). For ation of Effexor XRR), other SNRIs, and SSRIs, have been patients requiring discontinuation of opioids, a gradual down reported. Patients should be monitored for these symptoms ward titration is recommended since it is not known at what when discontinuing treatment. In clinical trials with Effexor 40 dose level the opioid may be discontinued without producing XRR), tapering was achieved by reducing the daily dose by 75 the signs and symptoms of abrupt withdrawal. mg at 1 week intervals, however, individualization of tapering For Smoking cessation using nicotine, very large reduction may be necessary. steps are recommended. The resultant clinical Success rates For paroxetine, the instructions for the discontinuation of are low, at 6-12% over placebo. treatment with Paxil.R state that recent clinical trials support- 45 Therefore, what is needed is a tapering system that pro ing the various approved indications for Paxil.R employed a vides for the complete cessation of any chemical or drug taper-phase regimen, rather than an abrupt discontinuation of Substance without the occurrence of withdrawal symptoms. treatment. The taper-phase regimen used in GAD and PTSD clinical trials involved an incremental decrease in the daily SUMMARY OF THE INVENTION dose by 10 mg/day at weekly intervals. When a daily dose of 50 20 mg/day was reached, patients were continued on this dose It is an object of the present invention to provide a chemical for 1 week before treatment was stopped. or drug Substance tapering system that provides for complete Furthermore, there is a trial and error mode in methods to cessation of and dependence on a chemical or drug Substance. be used to avoid withdrawal. For paroxetine, the instructions It is another object of the present invention to provide a for the discontinuation of treatment with PAXILCR) state that 55 chemical or drug tapering system that provides a Success rate symptoms associated with discontinuation of immediate-re of 70% or greater. It is a further object of the present invention lease paroxetine hydrochloride or PAXIL CRR) have been to provide a plurality of dosages in decrements over a suffi reported and further instruct to see the precautions. The cient time period that provides for complete cessation of and instructions go on to State that patients should be monitored dependence on a chemical or drug Substance. for these symptoms when discontinuing treatment, regardless 60 The present invention achieves these and other objectives of the indication for which PAXIL CRR) is being prescribed. by providing an effective treatment to achieve cessation of Like serotonin and norepinephrine reuptake inhibitors, chemical or drug use. The present invention requires very gradual reduction in the dose of paroxetine rather than abrupt gradual lowering of the blood levels for an extended period, cessation is recommended whenever possible. If intolerable e.g. 90-120 days or more. The extended period is required to symptoms occur following a decrease in the dose or upon 65 ensure that the decrease in the lowest blood level from the discontinuation of treatment, then resuming the previously previous lowest blood level cannot be more than 5%. Other prescribed dose may be considered. Subsequently, the physi wise, a more rapid decrease in chemical or drug blood levels US 8,163,731 B2 5 6 will not allow the brain and body to adapt to a new homeo In another embodiment of the present invention, the quan Stasis without untoward symptoms. tity of dosage forms in the kit is sufficient for administration One embodiment of the present invention includes a for ninety days or more or one hundred twenty days or more. method of reducing the concentration of a chemical or drug Another embodiment of the present invention includes a Substance in the blood that targets the same or similar recep 5 plurality of dosing regimens formulated for reducing the con tors as the normal neurotransmitters in the central or periph centration of a chemical or drug Substance in the blood eral nervous system to a level that no longer interferes with plasma that targets the same or similar receptors as the normal the normal neurotransmitters and their receptors. The method neurotransmitters in the central or peripheral nervous system. includes titrating an initial peak concentration of the chemical The plurality of dosing regimens includes a quantity of a or drug Substance in the blood for a predefined dosing period, 10 chemical or drug Substance contained in each of the plurality titrating a lowest concentration level of the chemical or drug of dosing regimens where the plurality of dosing regimens substance in the blood immediately before the end of the includes an initial dosing regimen and a plurality of Subse dosing period to determine the lowest concentration level of quent dosing regimens. Each dosing regimen defines a dosing the chemical or drug Substance, and providing a plurality of period and each dosing period contains a dosing amount of 15 the chemical or drug Substance that when administered Subsequent dosing periods wherein each Subsequent dosing ensures that the lowest concentration level of the chemical or period requires administration of a dosing amount of the drug Substance in the blood plasma for a Subsequent dosing chemical or drug Substance to ensure that the lowest concen period is decreased by not more than five percent of the lowest tration level of the chemical or drug substance in the blood concentration level in the blood plasma of a previous dosing plasma for the Subsequent dosing period is decreased by not period. The quantity of the chemical or drug Substance is more than five percent of the lowest concentration level of the Sufficient for administration for seventy days or more. previous dosing period and wherein the plurality of dosing In another embodiment of the present invention, the chemi periods added together extends the method for seventy days cal or drug Substance of the plurality of dosing regimens is O. O. selected from the group consisting of the original chemical or In another embodiment of the present invention, the 25 drug Substance in the blood plasma and compounds that are method includes a stabilizing concentration of the chemical agonists for the same receptor sites where the compounds are or drug Substance in the blood plasma when using a replace used as a replacement chemical or drug Substance for the ment chemical or drug Substance instead of using the original original chemical or drug Substance in the blood plasma. chemical or drug Substance. In still another embodiment of the present invention, the In still another embodiment of the present invention, the 30 quantity of the chemical or drug Substance in the plurality of method includes selecting a chemical or drug substance that dosing regimens includes one or more dosing regimens of the is the original chemical or drug Substance or compounds that replacement chemical or drug substance to stabilize the con are agonists for the same receptor sites as the original chemi centration of the replacement chemical or drug Substance in the blood plasma before administration of the plurality of cal or drug Substance. 35 Subsequent dosing regimens. In yet another embodiment of the present invention, the In yet another embodiment of the present invention, the method includes a plurality of subsequent dosing periods that, quantity of the chemical or drug Substance in the plurality of when added together, extends the method for ninety days or dosing regimens is Sufficient for administration for ninety more or one hundred twenty days or more. days or more or one hundred twenty days or more. A further embodiment of the present invention includes a 40 kit for reducing the concentration of a chemical or drug Sub BRIEF DESCRIPTION OF THE DRAWINGS stance in the blood plasma that targets the same or similar receptors as the normal neurotransmitters in the central or FIG. 1 is a graphic illustration of the actual dosage regimen peripheral nervous system. The kit includes a plurality of data for example 5 for an approximate 70 day regimen. dosage forms of the chemical or drug Substance packaged in 45 FIG. 2 is a graphic illustration of the dosage regimen data a plurality of decreasing dosing series where each dosing for example 5 plotted on semi log form. series defines a dosing period. Each dosing period contains a FIG. 3 is a graphic illustration of the dosage regimen data dosing amount of the chemical or drug Substance that when of the calculated peak and lowest concentration of buprenor administered ensures that the lowest concentration level of phine hydrochloride in the blood represented by Table 7 and the chemical or drug substance in the blood plasma for the 50 plotted in semi log form for a 90 day regimen. Subsequent dosing period is decreased by not more than five FIG. 4 is a graphic illustration of the dosage regimen data percent of the lowest concentration level in the blood plasma of the peak and lowest concentration of buprenorphine hydro of the previous dosing period. The quantity of dosage forms is chloride in the blood represented by Table 8 for a 120 day Sufficient for administration for seventy days or more. regimen and plotted in semi log form for a 120 day regimen. In still another embodiment of the present invention, the 55 chemical or drug Substance in the kit is selected from the DETAILED DESCRIPTION OF THE PREFERRED group consisting of the original chemical or drug Substance in EMBODIMENT the blood plasma and compounds that are agonists for the same receptor sites wherein the compounds are used as a Dependence on psychoactive Substances such as opioid replacement chemical or drug Substance for the original 60 drugs has been a major health issue across the globe for many chemical or drug Substance in the blood plasma. years. Among users, there is an increase in the transmission of In yet another embodiment of the present invention, the HIV and Hepatitis C, which, in effect, increases health care plurality of dosage forms in the kit includes one or more costs for the user but also for the community they effect. dosage forms of the replacement chemical or drug Substance A person can become dependent on psychoactive Sub to stabilize the concentration of the replacement chemical or 65 stances with regular drug use in two manners, physically and drug Substance in the blood plasma before administration of psychologically. Physically, the brain becomes used to or the plurality of Subsequent decreasing dosing series. adapts to the presence of the drug in order to function “nor US 8,163,731 B2 7 8 mally’. Psychoactive drugs affect the central nervous system in biologically available narcotic and thus feel more secure as and alter what the brain considers normal function. At the they are not experiencing even minor withdrawal symptoms. beginning of drug use, the user may experience a euphoria Accordingly, the drug rehabilitation protocol was altered to because the drug affects the nucleus accumbens, or the resemble the current protocol that will provide gradual brain’s “pleasure center'. Neurons in the nucleus accumbens reduced doses and blood levels, replacing the use of higher use the same neurotransmitter as dopamine, although each fixed doses. drug affects this area differently, drugs either stimulate Commercially available buprenorphine (Suboxone(R) & dopamine release or enhance its activity, directly or indi Subutex(R) is available in strengths of 8.0 mg as well as 2.0 rectly. Initially the body only needs a minimal amount of a mg. However, that these medications would not suffice for a 10 Successful program, because the 2.0 mg dose was too large Substance to function normally and attain the state of eupho and too steep cut-off. A 2.0 mg dose reduction of buprenor ria, however, over time and with chronic use, the body builds phine caused significant withdrawal symptoms in an experi a tolerance for the drug and therefore needs more of the drug to function normally. Additionally, chronic drug use results in enced or chronic user of narcotic type medications. As a less and less stimulation of the nucleus accumbens until even result, reduction in dosage was be tapered below 1.0 mg as 15 well as using two doses of buprenorphine daily for those tually it produces no state of euphoria. This physical depen patients who had very heavy daily narcotic use patterns (i.e. dence is a combination of an increased tolerance to a drug and over 240.0 mg of OxyContin R) daily). a physical need for the drug to function. During inception of development of multidose treatment The method and regimen for blood level reduction that led to the current invention, and using the then current described herein lead to gradual normalization of these state of art, buprenorphine troches for the treatment (not changes over an extended period of time. The brain that had maintenance) of opiate dependence was used on a patient that adapted to chronic chemical or drug use, now readapts to a was a 21 years old male who was using I.V. 5-8 bags of heroin chemical or drug-free state. daily. He was started on 3 mg of buprenorphine and remained Withdrawal refers to the signs and symptoms that appear on this dose for three days. After a two day period without when an individual becomes physically dependent on a drug 25 , an attempt was made to administer the opiate blocker and drug use is Suddenly discontinued or decreased in dosage. maltrexone which was intended to assure that a person is The appearance of withdrawal symptoms can be within a few indeed drug free and remained so. However, this treatment hours or after several days of discontinuation. The time did not succeed as severe withdrawal symptoms precipitated depends on the drug's elimination half-life. The discontinu by this treatment resulted in his to return to drug use. ation of drug use may produce a state of dysphoria, because 30 Many alterations in treatment protocols to prevent with the neurotransmitter levels within neural regions such as drawal were made. The alterations included a greater variety nucleus accumbens declines below normal levels. These sub of doses ranging from 8.0 to 4.0 mg administered in a deceas normal levels may be characterized by depression, anxiety, ing amount over time. At first the dose strengths varied from and craving. Other common signs of withdrawal are 8.0 mg administered once daily with a daily reduction of 2.0 increased heart rate and/or blood pressure, tremors, nausea, 35 mg until to 4.0 mg, and then to 2.0 mg. However during the hallucinations, body aches, and excessive Sweating, diarrhea, earliest use of buprenorphine, it was understood that to go night terrors, restless leg syndrome, vomiting, dehydration, from administering 3.0 mg or even 2.0 mg to sobriety was too formications (crawling skin), as well as vivid or disturbing steep a cut-off point (i.e. patient would experience challeng dreams of drug use. Some of the withdrawal symptoms them ing withdrawal symptoms) and that fixed doses do not serve selves require hospitalization, Such as hallucinations and sei 40 the patients well. Zures. Other possible serious risks include an increased dan A 6.0 mg dose was then added to the protocol. This length ger to self and/or others. ened the withdrawal period from three days to seven. This The preferred embodiment of the present invention incor change was occasioned by the observation that the drop from porates the use of a long term, controlled drug tapering regi 8.0 mg to 4.0 mg was all too frequently accompanied by a men coupled with blood titration to determine blood levels of 45 significant return of withdrawal symptoms and, at times, a the drug Substance in order to achieve the cessation of chemi return to use. cal or drug use. Unlike prior art approaches to treatment, the Despite these alterations in the treatment protocol the present invention achieves cessation of chemical or drug use results were still not what were expected. The observation by using a regimen that very gradually lowers blood levels for was made that a cut-off of 2.0 mg would cause a return of an extended period of time. A key aspect of the method and 50 withdrawal symptoms within 24 hrs and thus the likelihood of regimen of the present invention requires that the decrease in a return to drug use beforenaltrexone could be started. The the lowest blood level from the previous lowest blood level of data indicated that the downward transition or incremental the chemical or drug Substance cannot be more than five decrease needed to be Smoother. As a result, a 1.0 mg lozenges percent (5%). were administered This specific multidose strategy is also useful to inhibit 55 A fractional buprenorphine dose was administered to withdrawal symptoms associated with abrupt cessation medi reduce the severity of withdrawal symptoms. This strategy cations as noted in Section 2. was in response to ongoing withdrawal symptoms following Development of the Variable Multidose Treatment Proto the “conclusion of withdrawal or a “final 3.0 mg dose of col to Reduce Physical Symptoms of Withdrawal buprenorphine. To mitigate the withdrawal symptoms, a dose After several years of clinical experience in the use of 60 of 1.5 mg of buprenorphine was given to the patient. This buprenorphine, it became clear that a single dose in mg of particular treatment was unsuccessful as the ongoing with buprenorphine given over a short period of time would not drawal symptoms were too difficult for the patient who lead to a drug-free status. Buprenorphine taken Sublingually relapsed as a result. has a mean half-life of 12-37 hrs. If the dose is reduced Stepwise increments were amended to proceed in the sub rapidly, the patient reacts with both physical and emotional 65 1.0 mg dose range. The taper at this time was 1.0 mg, 0.75 mg. symptoms of withdrawal. By reducing the dose slowly, the 0.5 mg. to 0.25 mg then a four day period of blank troches patients experience a period where there is little or no decline followed by an upward taper of troches with naltrexone going US 8,163,731 B2 9 10 from 0.5 mg of naltrexone to 10.0 mg of naltrexone. With DemerolR) 50-1500 mg per day; Heroin intranasally or intra serial doses of 0.25 mg of buprenorphine many patients con venously 1 “bag” to 4 g per day; and Suboxone(R) 2-32 mg per tinued to report perceptible and, in Some cases, intolerable day. withdrawal symptoms. Since naltrexone is administered following the cessation of As a result of the ongoing objective patient observations narcotic, there can be no residual narcotic in a patient’s sys and patient's Subjective complaints of withdrawal symptoms, tem, otherwise the naltrexone will push the patient into with a 0.1 mg dose was introduced. Additionally, a dose of 1.5 mg drawal. Therefore, the patient must wait about a week before as well as a dose of 0.75 mg was added to the dose progression to start naltrexone, even with extremely low doses, doses that series. Although withdrawal complaints were limited, they may be considered to be homeopathic but are high enough to 10 cause withdrawal symptoms if the narcotic is not fully were still present, and generally in the late phases of treat washed out. As necessitated by the recognition that naltrex ment. The data indicated that in order to reduce the com one, even administered at 12.5 mg, causes a return of with plaints of withdrawal symptoms, the dose increments had to drawal symptoms for up to five days after the end of buprenor be further reduced in the Sub 2.0 mg taper range. A strategy of phine treatment. The patient has to wait at least five days, 0.1 mg decreases in dose was implemented when the patients 15 remaining opiate free, before naltrexone could start. reached the 4.0 mg dose range (i.e., 2.0 mg twice a day) and Psycholoclical Withdrawal 0.01 mg deceases in the below 1.0 mg range. The effect of this Another change in the protocol dealt with the growing change also to extended the withdrawal period to about six to awareness of the psychology of opiate dependence, or the eight weeks from four weeks. The extended treatment time, psychological withdrawal symptoms. Initially, all patients allowed for concentrating the treatment on the psychological were informed daily of the dose that they were to receive in side of the dependency after the physical dependency sub the office and the proposed dose schedule for their complete sided. This extension of service allowed for greater focus on detoxification. This clearly caused distress with the patients the emergence of cravings as the patients approached the 2.0 who would become panicky or anxious upon learning that mg barrier. they would receive a smaller dose today than yesterday and To further reduce the physical and psychological symp 25 that their treatment would likely end in four days time. The toms of withdrawal, the rate of taper or stepwise decrease in patients were exhibiting the psychological withdrawal Symp buprenorphine dose was reduced to 1.0 mg every other day toms associated with reducing the amount of opioid in their and doses were given twice a day. Although Successful for the body. most part in eliminating withdrawal symptoms, there contin Understanding psychological withdrawal symptoms, and ued to be a group of patients who were large users of longer 30 seeing how it complicated the withdrawal process, the proto col was changed to: a) make all of the lozenges look and taste acting narcotics such as Methadone and OxyContin R that the same and b) absence of discussions regarding dose with found that they continued to have significant withdrawal patients as it lead to unnecessary anxiety. Instead, the discus symptoms. An induction phase of treatment is expanded from sion is focused on withdrawal symptoms and craving type 3-5 days to 5-10 days before the withdrawal process is started. 35 symptoms. A craving is a dysphoric affective state that occurs In an effort to eliminate the last vestiges of withdrawal symp in the process of withdrawal from a drug of dependence in the toms, the taper was altered to reduce the dose to 5.0 mg every absence of NVD but may include physical symptoms of pain, other day. Additionally, the number of sub 0.1 mg doses malaise, insomnia, headache, anergia, anorexia, or vivid and administered was increased resulting in a transition of almost disturbing dreams of drug use. 100% of our patients safely and in a symptomless manner 40 Further observations indicated that to end the treatment from the opiate buprenorphine to the blocker naltrexone. The with a buprenorphine troche and then ask the patient to wait change further lengthened the treatment course from two five to seven days before starting on naltrexone would likely months to three or more months. The length of treatment was lead to relapse. Therefore, naltrexone was compounded into dependent upon the daily dose of narcotics taken prior to fractional doses starting at 1.0 mg. By so doing, the time with entering treatment. 45 no medication is shortened and the risk of any withdrawal As a result, all of the treatments ended when an individual symptoms is reduced by creating the blocking of opiate resi was successfully started on naltrexone, i.e., the individual due by naltrexone. was entirely off of narcotics. The protocol no longer stopped Rationale for Inhibition of Withdrawal Symptoms Associ when buprenorphine content of the lozenges was discontin ated with Cessation of Non-Opiates ued. Instead, the patients returned daily and were given 50 Most medications that have the potential for dependence blank lozenges. After a sufficient period to allow for a total are dosed so that they will be effective, i.e., they will resolve washout of residual buprenorphine, the patients were transi the target symptom be it pain, anxiety, seizures, depression tioned to naltrexone 0.5 mg in lozenge form. This concentra etc. In contrast, the target symptom of the multidose approach tion then was gradually increased to 10.0 mg. When a patient is the withdrawal symptom(s); a therapeutic dose is one that reached 10.0 mg naltrexone in lozenge form, they were 55 does not cause withdrawal symptoms. Any medication that moved to naltrexone PO. causes withdrawal symptoms upon abrupt cessation, when The methods described herein have been successful in withdrawn slowly according to the multidosing schedule con individuals who were using massive amounts of pain killer fers clinical benefit by reducing or eliminating physiological type narcotics, such as doses of Fentanyl as Actiq in excess of and/or psychological withdrawal symptoms. 1200mcgm #10 daily, as well as Methadone and illegal forms 60 Certain families of medications such as the benzodiaz of opiates (Heroin 4+ gm IV daily). Patients to be treated epines (Librium(R), Valium(R), Xanax(R), Klonopin(R), Ativan R, include those with the following exemplary drug use profiles: etc) have well known pathways that lead to their withdrawal Percocet R 500/10 mg, 5-30 tabs per day; Vicodin(R) 500/10 states. BenZodiazepines that are abruptly stopped cause mg, 5-30 tabs per day: OxyContinR 10-80 mg, 1-25 tabs per severe seizures as well as panic attacks. In addition, over time day; Methadone 10-400 mg per day: MSContin(R) 100-400 65 Some individuals develop a psychological dependence on this mg per day: Fentanyl 75 1200 mcgm per day: UltramR) type of medication as well as a physical one. For these indi 50-100 mg 10-50 tabs per day; Diluadid.R. 4-76 mg per day; viduals, a micro dose approach to cessation is the most clini US 8,163,731 B2 11 12 cally sound way to get a person off the drug. This approach with delusions of bodily dysfunction or discorporation. It is especially applicable for those subjects, who have become frequent and common for the patient to conclude that he is dependent on this class of medication and who also have a having a nervous breakdown, or 'going crazy' as an attempt concomitant alcohol dependence since the benzodiazepines to try to understand the process at hand, not understanding it and alcohol are seen as similar by the body. as withdrawal phenomena. With further progression, disori Abrupt cessation of a benzodiazepine in an active drinker entation to person and place occurs with full delirium, and can cause that person to increase their alcohol consumption. eventually withdrawal will finalize with tonic-clonic major For example, the effects of Xanax(R) withdrawal (as an motor seizure activity, generally singular in nature, although example) are described below. What has become clinically several cases of status have been reported. The last triad of apparent with Xanax(R) which appears to be somewhat differ 10 symptoms, hallucinosis, delirium and seizure, are classified ent than the other benzodiazepines is that the patient’s ability as major symptoms of XanaXR withdrawal and other symp to self-detox (longer acting benzodiazepines Such as toms of drugs in this category. The withdrawal syndrome can Klonopin(R/Valium(R) or be able to be gradually tapered off take from months, e.g., 2-6 months, up to two years to fully of the medication is markedly more difficult. Thus once the resolve. physiologic dependence has occurred with Xanax R, the abil 15 Another class of medication that is favorably withdrawn ity of the patient to discontinue use Successfully on their own using the multidose regimen of the present invention is SSRI is quite low, and medical assistance becomes of significant antidepressants, e.g., Paxil.R and Zoloft(R), as well as the non necessity in the majority of cases. The withdrawal syndrome SSRI antidepressant WellbutrinR). The methods are useful to from Xanax(R) and other benzodiazepines are quite similar, safely and effectively reduce and then cease dependence on with the exception that XanaX(R) has a much higher incidence antidepressants such as those that inhibit neuronal uptake of of panic attack and a bereavement type of emotional lability serotonin, norepinephrine, and/or dopamine. The listed with that is singularly more severe. Since the symptoms are almost drawal symptoms for Paxil.R are noted in the below chart and all internal, with a few physical or objective manifestations, are representative of other SSRI type antidepressants. Com the diagnosis of it can be very difficult. Patients have a diffi plaints of insomnia and “body shock” are terrifying to a cult time verbally describing what is occurring, and much of 25 person wishing to get off of this medication but finding that the descriptions often take on a quality or character reminis they subject to highly unpleasant and disruptive conse cent of the emotional or psychiatric problem for which they quences of Sudden cessation Such as: intense insomnia; originally began taking Xanax R, rather than a withdrawal extraordinarily vivid dreams; extreme confusion during wak symptom. ing hours; intense fear of losing sanity; steady feeling of The withdrawal syndrome is diagnosed based on the fol 30 existing outside of reality (depersonalization at times); lowing description of symptoms. In the early stage of with memory and concentration problems; panic attacks; severe drawal, there is a presentation of a sense of anxiety and mood swings (heightened irritability/anger); suicidal apprehension associated with increasing Subjective sense of thoughts; dizziness/vertigo; feeling of shocks (similar to mild tremorand mild bifrontal headache. This rapidly progresses electric one, running the length of your body); unsteady gait; to feelings of panic-like anxiety with tachycardia and palpi 35 slurred speech; headaches; profuse Sweating, e.g., at night; tations, as well as a rapidly progressing feeling of de-realiza muscle cramps; blurred vision; breaking out in tears; hyper tion, which is an altered sense of reality. Symptoms may also sensitivity to motion, Sounds, Smells; decreased appetite; be associated with marked startle response and a general nausea; abdominal cramping, diarrhea, loss of appetite; and/ amplification of most sensory input. As the withdrawal Syn or chills/hot flashes. drome progresses, there is a marked disturbance of proprio 40 Effexor R is another antidepressant with a withdrawal syn ception, with difficulty in ambulation relative to feeling drome that is reduced or eliminated using a tapering multi "dizzy' and “unsteady.” needing to use reference and physi dose strategy. Prior to the invention, individuals seeking to cal objects to steady oneself. With the proprioceptive problem cease medication struggled for years, e.g., two years. The increasing in severity simple acts such as Swallowing, signing schedule involved months skipping one day in between dose, one's name, talking or even buttoning a shirt can become 45 nine months later two days in between, and as of three months extremely difficult. many patients at this stage describe hot/ ago. 3 days in between, followed by 4 days in between. cold sensations and generalized myalgia. There is also a pro Withdrawal symptoms included a sensation of buZZing (elec gression of extreme emotional lability with sudden outbursts trical impulses) upon eye or head movement, nausea, diffi of crying or near panic levels of anxiety and fearfulness which culty concentrating, forgetfulness, numbness in feet, twitch will have sudden onset without clear connection to external 50 ing in the leg, disruptive sleep, night Sweats, blurred vision, events. Associated with this are frequent hypochodriacal hallucinations, and difficulty with daily activities including fears of morbid consequence from the sensations they are work and driving. Tapered multidosing as described herein feeling, such as fear of heart attack or stroke. Patients expe obviates the need to take off a week of work and allows the rience a type of emotional dysphoria which is very difficult individual being treated to function without marked distress. for them to verbalize, but which come very close by cumula 55 Often Such symptoms are rarely or not reported to physicians, tive description to a bereavement type of feeling that is very and physicians currently have no strategy for dealing with the painful emotionally. Additionally, the amplification of almost problem. Tapered multidosing gives the clinician the ability all sensory information coming into the brain, other than that to rapidly and safely get their patients off of medications that of taste, can produce many bizarre misinterpretation of sen pose a risk of Substantial discomfort if they are not discon sory stimulation ranging from feeling one’s teeth rotating in 60 tinued at a slow, steady and gradual pace. The strategy is also their sockets to parts of their bodies disassociating or “falling applicable to other antidepressants, e.g., the monoamine oxi Off. dase (MAO) inhibitor class of drugs such as Nardil R, Par As the withdrawal symptoms progress, illusionary and hal nate(R), and Marplan R, which may be associated with seizures lucinatory phenomena, predominately of a visual nature, if withdrawn rapidly. begin to manifest themselves, initially with patterns and geo 65 Anti-seizure medication also poses a withdrawal risk, e.g., metric shapes, and then into full-formed complex visual hal seizures, if abruptly terminated. However, tapered multidose lucinations. These symptoms also often become associated reduction schedules for Such drugs, e.g., barbiturates such as US 8,163,731 B2 13 14 phenobarbitols, Dilantin R, Depacote(R), reduce or eliminate reached a dosage of 0.1 mg, the dosage was then dropped to the risk of adverse effects of cessation of the drug. 0.05 mg, however, due to the patient suffering from with drawal symptoms, the dosage was increased to 0.1 mg, which EXAMPLE1 was administered for three days. At which point the dosage This patient began treatment with being administered a was again decreased to 0.05 mg a day for two days. The dosage of 6.0 mg of buprenorphine daily, via four lozenges. dosage was then decreased to 0.03 mg, then to 0.01 mg of the From there, the dosage of buprenorphine decreased daily by last day of treatment with buprenorphine. 0.5 mg, until the dosage was 2.0 mg. From there the patients The patient was then given a 1.0 mg dosage of Quinine. On dosage was decreased 0.2 mg a day until the dosage was 1.0 the last day the patient was given a 100 mg dosage of Sero mg. At that point, the dosage was reduced by 0.1 mga day and quel R. A Summary of the dosage can be seen in Table 1 the dosage of 0.2 mg was given for two days. When the patient below: TABLE 1 Prescription No. of No. Medication Dosage (mg) Lozenges Directions. Frequency 8412 Buprenorphine 6.OO 4 Take 1 Troche sublingually Troc Twice daily 8413 Buprenorphine 5.50 4 Take 1 Troche sublingually Troc Twice daily 8414 Buprenorphine S.OO 4 Take 1 Troche sublingually Troc Twice daily 841S Buprenorphine 4...SO 4 Take 1 Troche sublingually Troc Twice daily 8416 Buprenorphine 4.OO 4 Take 1 Troche sublingually Troc Twice daily 8417 Buprenorphine 3.SO 4 Take 1 Troche sublingually Troc Twice daily 8418 Buprenorphine 3.00 4 Take 1 Troche sublingually Troc Twice daily 8419 Buprenorphine 2.OO 4 Take 1 Troche sublingually Troc Twice daily 842O Buprenorphine 18O 4 Take 1 Troche sublingually Troc Twice daily 8421 Buprenorphine 1.60 4 Take 1 Troche Sublingually Troc Twice daily 8422 Buprenorphine 140 4 Take 1 Troche sublingually Troc Twice daily 8423 Buprenorphine 1.2O 4 Take 1 Troche sublingually Troc Twice daily 8424 Buprenorphine 1.OO 4 Take 1 Troche sublingually Troc Twice daily 8425 Buprenorphine O.90 4 Take 1 Troche sublingually Troc Twice daily 8426 Buprenorphine O.8O 4 Take 1 Troche sublingually Troc Twice daily 8427 Buprenorphine O.70 4 Take 1 Troche sublingually Troc Twice daily 8428 Buprenorphine O.6O 4 Take 1 Troche sublingually Troc Twice daily 8429 Buprenorphine OSO 4 Take 1 Troche sublingually Troc Twice daily 843O Buprenorphine O4O 4 Take 1 Troche sublingually Troc Twice daily 8431 Buprenorphine O.30 4 Take 1 Troche sublingually Troc Twice daily 8432 Buprenorphine O.2O 4 Take 1 Troche sublingually Troc Twice daily 8433 Buprenorphine O.2O 4 Take 1 Troche sublingually Troc Twice daily 8434 Buprenorphine O.10 4 Take 1 Troche sublingually Troc Twice daily 843S Buprenorphine O.OS 4 Take 1 Troche sublingually Troc Twice daily 8729 Buprenorphine O.10 4 Take 1 Troche sublingually Troc Twice daily 8730 Buprenorphine O.10 8 Take 1 Troche sublingually Troc Twice daily 8731 Buprenorphine O.10 8 Take 1 Troche sublingually Troc Twice daily 8732 Buprenorphine O.OS 8 Take 1 Troche sublingually Troc Twice daily 8854 Buprenorphine O.OS 8 Take 1 Troche sublingually Troc Twice daily 8855 Buprenorphine O.O3 8 Take 1 Troche sublingually Troc Twice daily US 8,163,731 B2 15 16 TABLE 1-continued Prescription No. of No. Medication Dosage (mg) Lozenges Directions. Frequency 8856 Buprenorphine O.O1 8 Take 1 Troche Sublingually Troche Twice daily 8438 Naltrexone Troche OSO 3 Take 1 Troche Sublingually Twice daily 8436 Quinine Troche 1.00 4 Take 1 Troche Sublingually Twice daily 8437 Quinine Troche 1.00 4 Take 1 Troche Sublingually Twice daily tel Seroquel 1OOOO 120 Tab ii-iv po qHS prn Onsomnia

EXAMPLE 2 15 TABLE 2-continued

Pre- Dos- No. of This patient began treatment with being administered a Scription age Loz dosage of 6.0 mg of buprenorphine daily, via nine lozenges. No. Medication (mg) enges Directions. Frequency From there the dosage of buprenorphine decreased daily by 2O 9054 Bupremorphine 1.60 9 Take 1 Troche Sublingually 0.25 mg, until the dosage was 2.0 mg. From there, the Troche Four Times Daily patient’s dosage was decreased 0.2 mg a day until the dosage 9055 Bupremorphine 140 9 Take 1 Troche Sublingually was 1.0 mg. At that point, the dosage was reduced by 0.1 mg 9056 TrocheBupremorphine 1.20 9 TakeFour Times1 Troche Daily Sublingually a day. When the patient reached a dosage of 0.1 mg, the OCle. Four Times Daily dosage was then dropped to 0.05 mg, the dosage was then 25 9057 Bupremorphine 1.00 9 Take 1 Troche Sublingually 0.03 mg, and finally 0.01 mg on the final day of treatment with 9058 Buprenorphinerocne 0.90 9 Fourake TimesI liroche Daily Sublingually of buprenorphine. OCle. Four Times Daily The patient was then given a 1.0 mg dosage of Quinine for 9059 Buprenorphine 0.80 9 Take 1 Troche sublingually OCle. Four Times Daily tWO days. On the last day the patient was given a 0.5 ng 906O Buprenorphine 0.70 9 Take 1 Troche Sublingually dosage of naltrexone. A Summary of the dosage can be seen in 30 OCle. Four Times Daily Table 2 below: 9061 Buprenorp hine 0.60 9 Take 1 Troc ne sub ingually OC Four Times Daily 9062 Buprenorphine 0.50 9 Take 1 Troche Sublingually TABLE 2 OCle. Four Times Daily 9063 Buprenorphine 0.40 9 Take 1 Troche Sublingually Pre- Dos- No. of 35 Troche Four Times Daily Scription age Loz- 9064 Bupremorphine 0.30 9 Take 1 Troche Sublingually No. Medication (mg) enges Directions. Frequency OCle. Four Times Daily 906S Buprenorphine 0.20 9 Take 1 Troche Sublingually 9013 Buprenorphine 6.OO 9 Take 1 Troche Sublingually Troche Four Times Daily Troche Four Times Daily 9066 Buprenorphine 0.10 9 Take 1 Troche Sublingually 9014 Bupremorphine 5.75 9 Take 1 Troche Sublingually 40 OCle. Four Times Daily Troche Four Times Daily 9067 Buprenorphine 0.05 9 Take 1 Troche Sublingually 901S Buprenorphine 5.50 9 Take 1 Troche Sublingually Troche Four Times Daily Troche Four Times Daily 9068 Buprenorphine 0.03 9 Take 1 Troche Sublingually 9016 Buprenorphine 5.25 9 Take 1 Troche Sublingually OCle. Four Times Daily Troche Four Times Daily 9069 Buprenorphine 0.01 9 Take 1 Troche Sublingually 9017 Buprenorphine 5.00 9 Take 1 Troche Sublingually Troche Four Times Daily Troche Four Times Daily 45 9070 Quinine Troche 1.00 9 Take 1 Troche Sublingually 9018 Buprenorphine 4.75 9 Take 1 Troche Sublingually Four Times Daily Troche Four Times Daily 9071 Quinine Troche 1.00 9 Take 1 Troche Sublingually 9019 Buprenorphine 4.50 9 Take 1 Troche Sublingually Four Times Daily Troche Four Times Daily 9072 Naltrexone OSO 4 Take 1 Troche Sublingually 902O Buprenorphine 4.25 9 Take 1 Troche Sublingually Troche Once Daily Troche Four Times Daily 50 9021 Buprenorphine 4.00 9 Take 1 Troche Sublingually Troche Four Times Daily 9022 Buprenorphine 3.75 9 Take 1 Troche Sublingually EXAMPLE 3 Troche Four Times Daily 9023 Buprenorphine 3.50 9 Take 1 Troche Sublingually Troche Four Times Daily ss. This patient began treatment with being administered a 9024 Buprenorphine 3.25 9 Take E. sublingually dosage of 7.5 mg of buprenorphine daily, via four lozenges. 9025 BuprenorphineOCle. 3.00 9 TakeFour 1limes Troche Lally Sublingually From there the dosage of buprenorphine decreased daily by Troche Four Times Daily 0.5 mg, until the dosage was 2.0 mg. From there, the patients 9026 Buprenorphine 2.75 9 Take E. sublingually dosage was decreased 0.2 mg a day until the dosage was 1.0 9027 BupremorphineOCle. 2.50 9 TakeFour 1limes Troche Lally siblingually At that point, the dosage was reduced by 0.1 mg a day. Troche Four Times Daily When the patient reached a dosage of 0.1 mg, the dosage was 9028 Bupremorphine 2.25 9 Take 1 Troche Sublingually then dropped by 0.02 mg each day until finally the dosage was rocne Four Times Daily mg on the final day of treatment with of buprenorphine. 9029 Buprenorphine 2.00 9 Take 1 Troche Sublingually The patient was then given a 1.0 mg dosage of Quinine for 9053 BupremorphineOCle. 1.80 9 TakeFour Times1 Troche Daily siblingually 65 four days. On the last day the patient was given a 0.5 mg Troche Four Times Daily dosage of naltrexone. A Summary of the dosage can be seen in Table 3 below: US 8,163,731 B2 17 TABLE 3 Dosage No. of Prescription No. Medication (mg) Lozenges Directions. Frequency 8892 Buprenorphine 7.50 4 Take 1 Troche Sublingually Troche Twice Daily 8893 Buprenorphine 7.OO 4 Take 1 Troche Sublingually Troche Twice Daily 8894 Buprenorphine 6.50 4 Take 1 Troche Sublingually Troche Twice Daily 8895 Buprenorphine 6.OO 4 Take 1 Troche Sublingually Troche Twice Daily 8896 Buprenorphine 5.50 4 Take 1 Troche Sublingually Troche Twice Daily 8897 Buprenorphine S.OO 4 Take 1 Troche Sublingually Troche Twice Daily 88.98 Buprenorphine 4...SO 4 Take 1 Troche Sublingually Troche Twice Daily 8899 Buprenorphine 4.OO 4 Take 1 Troche Sublingually Troche Twice Daily 89.00 Buprenorphine 3.SO 4 Take 1 Troche Sublingually Troche Twice Daily 89.01 Buprenorphine 3.00 4 Take 1 Troche Sublingually Troche Twice Daily 89.02 Buprenorphine 2.50 4 Take 1 Troche Sublingually Troche Twice Daily 89.03 Buprenorphine 2.OO 4 Take 1 Troche Sublingually Troche Twice Daily 8904 Buprenorphine 18O 4 Take 1 Troche Sublingually Troche Twice Daily 890S Buprenorphine 1.60 4 Take 1 Troche Sublingually Troche Twice Daily 89.06 Buprenorphine 140 4 Take 1 Troche Sublingually Troche Twice Daily 8907 Buprenorphine 1.20 4 Take 1 Troche Sublingually Troche Twice Daily 89.08 Buprenorphine 1.OO 4. Take 1 Troche Sublingually Troche Twice Daily 89.09 Buprenorphine O.90 4 Take 1 Troche Sublingually Troche Twice Daily 8910 Buprenorphine O.80 4 Take 1 Troche Sublingually Troche Twice Daily 8911 Buprenorphine O.70 4 Take 1 Troche Sublingually Troche Twice Daily 8912 Buprenorphine O.60 4 Take 1 Troche Sublingually Troche Twice Daily 8913 Buprenorphine O.SO 4 Take 1 Troche Sublingually Troche Twice Daily 8914 Buprenorphine O40 4 Take 1 Troche Sublingually Troche Twice Daily 891S Buprenorphine O.30 4 Take 1 Troche Sublingually Troche Twice Daily 8916 Buprenorphine O.20 4 Take 1 Troche Sublingually Troche Twice Daily 8917 Buprenorphine O.10 4 Take 1 Troche Sublingually Troche Twice Daily 8918 Buprenorphine O.O8 4 Take 1 Troche Sublingually Troche Twice Daily 8919 Buprenorphine O.O6 4 Take 1 Troche Sublingually Troche Twice Daily 892O Buprenorphine O.OS 4 Take 1 Troche Sublingually Troche Twice Daily 8921 Buprenorphine O.O3 4 Take 1 Troche Sublingually Troche Twice Daily 8922 Buprenorphine O.O1 4 Take 1 Troche Sublingually Troche Twice Daily 8923 Quinine Troche 1.OO 4 Take 1 Troche Sublingually Twice Daily 8924 Quinine Troche 1.OO 4 Take 1 Troche Sublingually Twice Daily 892S Quinine Troche 1.OO 4 Take 1 Troche Sublingually Twice Daily 8926 Quinine Troche 1.OO 4 Take 1 Troche Sublingually Twice Daily 8927 Naltrexone Troche O.SO 4 Take 1 Tro C he sublingually Once Daily US 8,163,731 B2 19 20 EXAMPLE 4 TABLE 5 This patient began treatment having buprenorphine being Day PM Total BN administered a dosage of 4.0 mg of buprenorphine. Typically, ng 8 ng 16 ng a patient is given two doses of medication, at the same amount ng 8 ng 16 ng of buprenorphine, daily spaced approximately 12 hours apart ng 7.5 ng 15.5 ng and each dose is given for about two days. From there the each ng 7.5 ng 15 ng new dosage of buprenorphine decreased overtime by 10%, ng 7 ng 14.5 ng ng 7 ng 14 ng until dosage 16, at which point, the patient's dosage was ng 6.5 ng 13.5 ng decreased 15% for three dosages. At that point, the dosage 10 ng 6.5 ng 13 ng was reduced by 20% for each dosage over the course of two ng 6 ng 12.5 ng dosages. The next two dosages were reduced 25%. The dos 1 ng 6 ng 12 ng ages from dosage 23 to dosage 30 were reduced by another ng 5.5 ng 11.5 ng ng 5.5 ng 11 ng 30% per dosage. A Summary of the dosage can be seen in ng 5 ng 1O.S ng Table 4 below: 15 ng 5 ng 10 ng ng 4.5 ng 9.5 ng TABLE 4 ng 4.5 ng ng ng 4 ng 8.5 ng Dosage Buprenorphine % ng 4 ng ng No. (mg) Decrease ng 3.5 ng 7.5 ng ng 3.5 ng ng 1 4.OO O ng 3 ng 6.5 ng 2 3.60 O ng 3 ng ng 3 3.24 O ng 2.75 ng 5.75 ng 4 2.92 O 2.75 ng 2.75 ng 5.5 ng 5 2.62 O 2.75 ng 2.5 ng 5.25 ng 6 2.36 O 2.5 ng 2.5 ng ng 7 2.13 O 25 2.5 ng 2.25 ng 4.75 ng 8 1.91 O 2.25 ng 2.25 ng 4.5 ng 9 1.72 O 2.25 ng 2 ng 4.25 ng 10 1.55 O ng 2 ng ng 11 1.39 O ng 1.8 ng 3.8 ng 12 1.26 O 1.8 ng 1.8 ng 3.6 ng 13 1.13 O 30 1.8 ng 1.6 ng 3.4 ng 14 1.02 O 1.6 ng 1.6 ng 3.2 ng 15 O.92 O 1.6 Ing 1.4 Ing Ing 16 O.82 5 1.4 ng 1.4 ng 2.8 ng 17 O.70 5 1.4 ng 1.2 ng 2.6 ng 18 O.60 5 1.2 ng 1.2 ng 2.4 ng 19 O.S1 2O 35 1.2 ng 1.O ng 2.2 ng 2O O40 2O 1.O ng 1.O ng ng 21 O.32 25 1.O ng O.9 ng 1.9 ng 22 O.24 25 O.9 ng O.9 ng 1.8 ng 23 O.18 30 O.9 ng O.8 ng 1.7 ng 24 O.13 30 O.8 ng O.8 ng 1.6 ng O.8 ng 0.7 ng 1.5 ng 25 O.09 30 40 26 O.O6 30 0.7 ng 0.7 ng 1.4 ng 27 O.04 30 0.7 ng O6 ng 1.3 ng 28 O.O3 30 O.6 ng O6 ng 1.2 ng 29 O.O2 30 O.6 ng O.S ng 1.1 ng 30 O.O1 30 O.S ng O.S ng 1.O ng O.S ng 0.4 ng O.9 ng 45 0.4 ng 0.4 ng O.8 ng 0.4 ng O.3 ng 0.7 ng EXAMPLE 5 O.3 ng O.3 ng O6 ng O.3 ng O.2 ng O.S ng O.2 ng O.2 ng 0.4 ng This patient began treatment having buprenorphine being O.2 ng O.1 ng O.3 ng administered a dosage of 8.0 mg of buprenorphine, twice a 50 O.1 ng O.1 ng O.2 ng O.1 ng O.08 ng O.18 ng day. Typically, a patient is given two doses of medication, at O.08 ng O.08 ng O16 ng the same amount of buprenorphine, daily spaced approxi O.08 ng O.O6 ng O.14 ng mately 12 hours apart and each dose is given for about two O.O6 ng O.O6 ng O.12 ng days. Each two-day period is defined as a dosing period. The O.O6 ng O.04 ng O.1 ng decrease in the dosing amount per dosing period was 0.5 mg 55 O.04 ng O.04 ng O.08 ng until 6 mg was reached and then each dosing amount per O.04 ng O.O3 ng O.O7 ng O.O3 ng O.O3 ng O.O6 ng dosing period was decreased by 0.25 mg. At 4 mg. the dosing O.O3 ng O.O2 ng O.OS ng amount per period was decreased by 0.2 mg until 2 mg was O.O2 ng O.O2 ng O.04 ng reached and then each dosing amount per dosing period was O.O2 ng O.O1 ng O.O3 ng decreased by 0.02 mg. At 0.08 mg, the dosing amount per 60 O.O1 ng O.O1 ng O.O2 ng period was then decreased by 0.01 mg until 0.0 mg was O.O1 ng O ng O.O1 ng reached. The total days of the decreasing regimen was 71 Quinine days. A placebo was given for 4-5 days before naltrexone 72 ng ng administration began. FIG. 1 shows a graphical representa 73 ng ng tion of the rate of decline of the amount of buprenorphine 65 74 ng ng administered and a Summary of the dosage can be seen in 75 ng ng Table 5 below: US 8,163,731 B2 21 22 TABLE 5-continued treatment of patients on agents that included buprenorphine, codeine, fentanyl, heroin (diacetylmorphine), hydrocodone, Day AM PM Total BN hydromorphone, methadone, morphine, oxycodone, propo Naltrexone Syphene, , other opiates, and non-opiates Such as . The results indicated that the highest Success 76 O.S ng ng 77 O.S ng 0.5 mg 1 ng rate in drug cessation was achieved beyond 90 days. The final 78 1 ng 1 mg 2 ng results by treatment days using a replacement narcotic com 79 2 ng 2 mg 4 ng pound buprenorphine hydrochloride that achieved calculated 8O 5 ng 5 mg ng blood levels of no greater than five percent (5%) reduction Vivitrol (naltrexone IMLA) 10 or naltrexone 50 mg from the previous period are illustrated in Table 6 TABLE 6 It was further discovered that there were additional prob lems that appeared during the 71 day regimen as it relates to Total Successful 15 the concentration levels of the drug in the blood stream. These 1-30 days 75 38 50.7% problems with dosing and withdrawal issues occurred around 31-60 days 52 39 75.0% the fiftieth day of the regimen. Consequently, the data of Table 61-90 days 21 19 90.5% 6 was then plotted on a semi log. FIG. 2 shows a graphical representation of the dosing regimen plotted as a log scale. It appears that the curve is closely linear over the first fifty days To confirm these findings, numerical tabulations for mul but then declines more rapidly. A review of the dosing data tidosing involving buprenorphine for ninety (90) and one indicated that the decrease in dosing and the linearity of the hundred twenty (120) days confirm the gradual blood level log curve was closely tied to the relative difference of the changes required for Successful cessation. The original data dosing amount in a Subsequent dosing period to the dosing contains data at different dosing levels of 8 mg, 12 mg, 16 mg, amount in the previous dosing period. The problem was deter 25 and 24 mg. Some of the data (the first 15 days of data of the 90 mined to be the lowest level of the drug substance present in days) for the 8 mg and 24 mg is shown in Table 7 for the the blood plasma before the next dosing amount in the next 90-day regimen while FIG.3 shows a graphical illustration of dosing period. all of the data showing the peak and lowest level concentra From databased on high success rates (90% or greater) in tions for the 90-day regimen. Because peak concentration of achieving freedom from physical dependence to opioids and 30 a drug Substance in the blood typically occurs about 1 hour related Substances using specific gradually decreasing but after taking, blood concentration levels were calculated from measured doses, and projected blood levels based on the empirical data 1 hour after a dose is administered and imme pharmacokinetic profile of the replacement narcotic diately before the next dose is administered to obtain peak buprenorphine hydrochloride that has an opioid agonist concentration and lowest level concentration. The tapering is effect, it was concluded that blood level reductions of no 35 performed in a gradual decreasing format based on a log greater than five percent (5%) per day from the previous day curve similar to the log curve of the actual data of the first can lead to Successful cessation of use. The data included the 40-50 days of Table 5. TABLE 7

Multidose Multidose Dose 90 Change 90 Change Time Dose days Trough from days Trough from (day) time(hr) ng/mL 8 mg ng mL Slope prev ng/mL 24 mg ng/mL Slope prev O.O O O.OO O.OO O.OO O.OO O.O 1 2.98 S.90 O.S 12 O.36 O.36 0.79 0.79 O.S 13 3.20 6.49 1.O 24 O.S9 O.S9 1.32 1.32 1.O 25 3.32 7.01 1.5 36 0.72 0.72 1.71 1.71 1.5 37 3.45 7.27 2.0 48 O.82 O.82 1.97 1.97 2.0 49 3.41 740 2.5 60 O.86 O.86 2.13 2.13 2.5 61 3.45 7.42 3.0 72 O.89 O.89 2.23 2.23 3.0 73 3.36 7.43 3.5 84 O.89 O.89 2.28 2.28 3.5 85 3.36 7.32 4.0 96 O.89 O.89 2.28 2.28 4.0 97 3.21 7.15 4.5 108 O.87 O.87 -0.040 -2.2% 2.26 2.26 -0.040 -0.9% 4.5 109 3.19 7.03 S.O 120 O.86 O.86 -0.020 -1.1% 2.22 2.22 -0.080 -1.8% S.O 121 3.18 6.90 5.5 132 O.84 O.84 -0.040 -2.3% 2.17 2.17 -0.1OO -2.3% 5.5 133 3.06 6.65 6.O 144 O.81 O.81 -O.O60 -3.6% 2.11 2.11 -0.120 -2.8% 6.O 145 3.03 6.48 6.5 156 0.79 O.79 -0.040 -2.5% 2.04 2.04 -0.140 -3.3% 6.5 157 2.87 6.30

US 8,163,731 B2 25 26 TABLE 8-continued

Multidose Multidose Dose Dose 120 days Change 120 days Change Time Time ng/mL Trough from ng mL Trough from (day) (hr) (a8 mg ng/mL Slope prev (a)24 mg ng/mL. Slope prev 6.O 144 O.88 O.88 -0.040 -2.2% 2.28 2.28 -O.O80 -1.7% 6.O 145 3.20 7.05 6.S 156 O.86 O.86 -0.040 -2.3% 2.23 2.23 -0.100 -2.2% 6.5 157 3.18 6.91 7.0 168 O.85 O.85 -0.020 -1.2% 2.18 2.18 -0.100 -2.2% 7.O 169 3.06 6.76 7.5 18O O.82 O.82 -0.060 -3.5% 2.12 2.12 -0.120 -2.8% 7.5 181 3.03 6.60 8.0 192 O.80 O.80 -0.040 -2.4% 2.06 2.06 -0.120 -2.8% 8.0 193 3.01 6.43 8.S. 204 O.78 O.78 -0.040 -2.5% 2.00 2.00 -O.12O -2.9% 8.S. 205 2.86 6.26 9.O 216 0.75 O.75 -0.060 -3.8% .93 .93 -O.140 -3.5% 9.0 217 2.83 6.08 9.S 228 0.73 O.73 -0.040 -2.7% 86 86 -0.140 -3.6% 9.S 229 2.81 S.90 O.O 240 0.72 O.72 -0.020 -1.4% 8O 8O -0.120 -3.2% O.O 241 2.80 5.84 0.5 252 O.71 O.71 -0.020 -1.4% 75 75 -O.1OO -2.8% 0.5 253 2.61 5.67 1.O 264 O.69 O.69 -0.040 -2.8% 70 70 -O.1OO -2.9% 1.0 26S 2.58 S.49 1.5 276 O.67 O67 -0.040 -2.9% .64 .64 -O.12O -3.5% 1.5 277 2.57 5.32 2.0 288 O.66 O66 -0.020 -1.5% 59 59 -O.1OO -3.0% 2.O 289 2.56 S.26 2.S. 300 O.65 O.65 -0.020 -1.5% 54 54 -0.100 -3.1% 2.S 301 2.33 5.08 3.O 312 O.63 O.63 -0.040 -3.1% 49 49 -O.1OO -3.2% 3.O 313 2.31 4.92 3.S 324 O.61 O.61 -0.040 -3.2% .44 .44 -0.100 -3.4% 3.5 325 2.29 4.74 4.O 336 O60 O60 -0.020 -1.6% 39 39 -O.1OO -3.5% 4.0 337 2.28 4.69 4.5 348 O.S9 O59 -0.020 -1.7% 35 35 -O.O80 -2.9% 4S 349 2.27 4.51 S.O 360 O.S9 O.S9 OOOO -0.0% 31 31 -O.O80 -3.0% S.O 361 2.04 4.46 5.5 372 0.57 O57 -0.040 -3.4% 28 28 -O.O60 -2.3% 5.5 373 2.02 4.34 6.O 384 0.55 O55 -0.040 -3.5% .24 .24 -O.O80 -3.1% 6.O 385 2.00 4.18 6.5 396 O.S4 O54 -0.020 -1.8% 2O 2O -O.O80 -3.2% 6.5 397 1.99 4.14 7.O 408 O.S3 O53 -0.020 - 1.9% 17 17 -O.O60 -2.5% 7.O 409 1.98 3.98 7.5 420 O.S2 O-52 -0.020 - 1.9% 13 13 -O.O80 -3.4% 7.S 421 1.97 3.95 -0.040 -1.8% 8.0 433 1.84 3.82 8.5 444 OSO OSO -0.020 -2.0% O7 O7 -O.O80 -3.6% 8.S 445 1.83 3.79 9.O 456 O49 O49 -0.020 -2.0% OS OS -0.040 -1.9% 9.O 457 1.82 3.63 9.S 468 O48 O48 -0.020 -2.0% O2 O2 -O.O60 -2.9% 9.S 469 1.69 3.60 2O.O 48O O.47 O.47 -0.020 -2.1% O.99 O.99 -O.O60 -2.9% 2O.O 481 1.67 3.58

Although the preferred embodiments of the present inven 55 symptoms wherein the initial dosing regimen has at least tion have been described herein, the above description is one predefined dosing period of at least two days with merely illustrative. Further modification of the invention doses taken at least two times per day; herein disclosed will occur to those skilled in the respective titrating a lowest concentration level of the buprenorphine arts and all such modifications are deemed to be within the 60 or a pharmaceutically acceptable salt thereof in the Scope of the invention as defined by the appended claims. blood at the end of the initial dosing regimen or imme What is claimed is: diately before a second or later dose of the initial dosing 1. A method of treating opioid dependence while minimiz regimen is taken; and ing withdrawal symptoms, the method comprising: providing a plurality of dosages of the buprenorphine or a providing an initial dosing regimen of buprenorphine or a 65 pharmaceutically acceptable salt thereof plurality of pharmaceutically acceptable salt thereof, the initial dos Subsequent dosing periods wherein each Subsequent ing regimen being Sufficient to minimize withdrawal dosing period of the plurality of dosing periods is at least US 8,163,731 B2 27 28 two days with doses taken at least two times per day and a concentration in the blood for the next Subsequent provides a dosing amount that is less than the dosing series that is at least ninety-five percent of the lowest amount of the immediately preceding dosing period, the concentration level in the blood of the previous dosing dosing amount in each Subsequent dosing period pro series. viding a lowest concentration level in the blood of the 5 5. The kit of claim 4 wherein the quantity of dosage forms buprenorphine or a pharmaceutically acceptable salt is sufficient for administration for ninety days or more. thereof for the associated dosing period that is equal to at 6. The kit of claim 4 wherein the quantity of dosage forms least ninety-five percent of the lowest concentration in is sufficient for administration for one hundred twenty days or the blood of the buprenorphine or a pharmaceutically O. acceptable salt thereof of the immediately preceding 10 7. A plurality of dosing regimens formulated for treating dosing period and wherein the method extends for no opioid addiction that provides for minimizing withdrawal less than sixty days. symptoms, the plurality of dosing regimens comprising: 2. The method of claim 1 wherein the plurality of subse a quantity of buprenorphine or a pharmaceutically accept quent dosing periods added together extends the method for able salt thereof contained in each of the plurality of ninety days or more. 15 dosing regimens wherein the plurality of dosing regi 3. The method of claim 1 wherein the plurality of subse mens includes an initial dosing regimen of at least two quent dosing periods added together extends the method for days with doses taken at least two times per day and a one hundred twenty days or more. plurality of Subsequent decreasing dosing regimens 4. A kit for treating opioid addiction while minimizing wherein each dosing regimen contains a dosing amount withdrawal symptoms, the kit comprising: for at least two days with doses taken at least two times a plurality of dosage forms of buprenorphine or a pharma per day of the buprenorphine or a pharmaceutically ceutically acceptable salt thereof the plurality of dosage acceptable salt thereof that when administered ensures forms being packaged in a plurality of decreasing dosing that the lowest concentration level in the bloodplasma of series, the plurality of dosage forms contains an initial the buprenorphine or a pharmaceutically acceptable salt dosing amount of buprenorphine or a pharmaceutically 25 thereof for a Subsequent dosing regimen is equal to at acceptable salt thereof for an initial dosing series suffi least ninety-five percent of the lowest concentration cient to minimize withdrawal symptoms wherein the level in the blood plasma of the immediately preceding initial dosing series provides doses to be taken at least dosing regimen and wherein the quantity of the two times per day and for at least two days and a dosing buprenorphine or a pharmaceutically acceptable salt amount of the buprenorphine or a pharmaceutically 30 thereof is sufficient for administration for no less than acceptable salt thereof in each Subsequent decreasing sixty days. dosing series provides doses to be taken at least two 8. The plurality of dosing regimens of claim 7 wherein the times per day and for at least two days that when admin quantity of the buprenorphine or a pharmaceutically accept istered ensures that the lowest concentration level in the able salt thereof is sufficient for administration for ninety blood of the buprenorphine or a pharmaceutically 35 days or more. acceptable salt thereof for the Subsequent dosing series 9. The plurality of dosing regimens of claim 7 wherein the is equal to at least ninety-five percent of the lowest quantity of the buprenorphine or a pharmaceutically accept concentration level in the blood of the immediately pre able salt thereof is sufficient for administration for one hun ceding dosing series and wherein the quantity of dosage dred twenty days or more. forms is sufficient for administration for no less than 40 10. The method of claim 1 wherein the plurality of subse sixty days; and quent dosing periods added together extends the method for instructions to administer the initial dosing amount for an seventy days or more. initial dosing series to minimize withdrawal symptoms, 11. The kit of claim 4 wherein the quantity of dosage forms and to determine the lowest concentration level in the is sufficient for administration for seventy days or more. blood of the buprenorphine or a pharmaceutically 45 12. The plurality of dosing regimens of claim 7 wherein the acceptable salt thereof for the initial dosing series quantity of the buprenorphine or a pharmaceutically accept whereby the determined lowest concentration level in able salt thereof is sufficient for administration for seventy the blood of the initial dosing series is the value used for days or more. determining the Subsequent lowest concentration value for the next Subsequent dosing series to thereby provide UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. : 8,163,731 B2 Page 1 of 1 APPLICATIONNO. : 12/1951.43 DATED : April 24, 2012 INVENTOR(S) : Kenneth C. Slater et al. It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

In the Claims

In column 26, claim 1, line 65, after “acceptable salt thereof insert --for a--.

Signed and Sealed this Tenth Day of July, 2012

David J. Kappos Director of the United States Patent and Trademark Office