US 20150258111A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0258111A1 Maillet et al. (43) Pub. Date: Sep. 17, 2015

(54) METHODS AND COMPOSITIONS FOR Publication Classification REDUCING TOLERANCE TO OPOD ANALGESCSUSING BOGAINE AND (51) Int. Cl. DERVATIVES THEREOF A613 L/55 (2006.01) (52) U.S. Cl. (71) Applicant: DemeRx, Inc., Fort Lauderdale, FL (US) CPC ...... A6 IK3I/55 (2013.01) (72) Inventors: Emeline Maillet, Miami, FL (US); Lawrence Friedhoff, River Vale, NJ (57) ABSTRACT (US) (21) Appl. No.: 14/635,871 A method for modulating tolerance to an opioid analgesic in (22) Filed: Mar. 2, 2015 a patient undergoing opioid analgesic therapy, the method comprising interrupting or administering concurrently with Related U.S. Application Data said opioid analgesic therapy an amount of ibogaine, ibogaine (63) Continuation of application No. 61/952,743, filed on derivative, or pharmaceutically acceptable salt and/or Solvate Mar. 13, 2014. thereof. US 2015/025811 1 A1 Sep. 17, 2015

METHODS AND COMPOSITIONS FOR resensitization. In one aspect, the resensitized patient obtains REDUCING TOLERANCE TO OPOD improved therapeutic effect from the same dose of the opioid ANALGESCSUSING IBOGAINE AND analgesic compared to before resensitization. DERVATIVES THEREOF 0008. The use of ibogaine for the modulation of tolerance to opioid analgesic agents is limited due to potentially adverse CROSS-REFERENCE TO RELATED side effects. For example, ibogaine exhibits undesirable APPLICATIONS stimulant and hallucinogenic properties, and in addition, can 0001. This application claims benefit from U.S. Provi induce tremors. At conventional doses, ibogaine causes sional Application No. 61/952,743, filed Mar. 13, 2014, adverse side effects in a majority of patients receiving treat which is hereby incorporated by reference in its entirety. ment. Thus, the use of ibogaine to modulate opioid tolerance is generally not favored due to the adverse side effects that can FIELD OF THE INVENTION result from receiving a therapeutic dose according to conven tional known methods. 0002 This invention is directed to methods for reducing 0009. It has been discovered that the use of ibogaine, tolerance to opioids in a patient undergoing opioid analgesic ibogaine derivative, or pharmaceutically acceptable salt and/ treatment for pain comprising treating the patient with or Solvate thereof imparts a dose dependent prolongation of ibogaine, an ibogaine derivative, or a pharmaceutically the treated patient’s QT interval, rendering higher dosing of acceptable salt and/or solvate thereof (hereinafter referred to ibogaine unacceptable. A prolonged QT interval is a marker as “ibogaine') at a therapeutic dosage. of potential Torsades de Pointes, a serious arrhythmia that can result in death. For reasons that are not apparent, this prolon STATE OF THE ART gation increases in opioid addicted patients as compared to 0003. Addictive opioid analgesic agents such as morphine healthy individuals. Heretofore, it was unclear whether a are well-known and exceptionally potent analgesics. Such therapeutic dose of ibogaine could be found that resulted in opioids operate as mu receptor agonists. Upon administra QT interval prolongation within an acceptable range. It is tion, opioids initiate a cascade of biological events including expected that other compounds that share ibogaine's core increased serotonin and dopamine expression. As is well structure will have a similar prolongation effect on QT inter known, continued use of many Such opioids (especially at val. See, U.S. Provisional Patent Application No. 61/945,746 high doses) carries a significant risk of dependency/addiction. filed Feb. 27, 2014 entitled METHOD FOR ACUTE AND Indeed, potential addiction to such opioids is a serious issue LONG-TERM TREATMENT OF DRUG ADDICTION, that limits the therapeutic use of addictive opioids as analge which application is incorporated by reference in its entirety. sic agents. For example, the use of morphine as an analgesic 0010. The current invention is predicated on the surprising is common among end stage patients suffering from serious discovery that treatment with a narrow dosage range of pain where addiction is no longer a concern. ibogaine, ibogaine derivative, orpharmaceutically acceptable 0004 Drug tolerance to opioid analgesics is common, and salt and/or solvate thereof, between greater than about 1 may be psychological and/or physiological. A patient who mg/kg body weight and about 8 mg/kg body weight, provides has developed tolerance to the opioid analgesic is not neces atherapeutic modulation of intolerance to opioid analgesics. sarily addicted to or misusing the analgesic. Drug tolerance Preferably, the dose range that provide both therapeutic occurs when the patient’s reaction to the drug is reduced, results and an acceptable QT interval prolongation of less requiring an increase in dose to achieve the same desired than 50 milliseconds is between about 1.3 mg per kg body effect. There are several potential methods for how tolerance weight and no more than about 4 mg per kg body weight and, develops, including receptor desensitization, receptor phos more preferably between about 1.3 mg per kg body weight phorylation, receptor internalization or down-regulation, and and no more than about 3 mg per kg body weight, or any up-regulation of inhibitory pathways. Subrange or Subvalue within the aforementioned ranges. 0005 Drug tolerance requires that the dosage of analgesic 0011. In a preferred embodiment, the narrow therapeutic be increased in order to provide Sustained analgesic effect. doses of ibogaine, ibogaine derivative, or pharmaceutically However, high doses of opioids may lead to serious compli acceptable salt and/or Solvate described above do not prolong cations and side effects, including physical dependence, the QT interval to unacceptable levels in human patients. In addiction, respiratory depression, nausea, sedation, euphoria Some embodiments, patients will be administered therapeutic or dysphoria, decreased gastrointestinal motility, and itching. doses of ibogaine, ibogaine derivative, or pharmaceutically 0006. It would be beneficial to provide a method for modu acceptable salt and/or Solvate thereof in a clinical setting with lating opioid analgesic tolerance in a patient taking one or cardiac monitoring. In some embodiments, the patient will be more opioid analgesics for the treatment of pain. pre-screened to evaluate tolerance for prolongation of QT interval, e.g., to determine whether the patient has any pre SUMMARY existing cardiac conditions which would disqualify them 0007. This invention is directed, in part, to the use of from treatment with ibogaine. ibogaine to modulate tolerance to addictive opioid analgesic 0012. In one embodiment, ibogaine, ibogaine derivative, agents in a patient who has developed or is at risk of devel or pharmaceutically acceptable salt and/or Solvate thereof is oping a tolerance for the analgesic. In such methods, effective administered concurrently with the opioid analgesic. In one analgesia can be achieved in a patient while resensitizing the embodiment, ibogaine, ibogaine derivative, or pharmaceuti patient to the addictive opioid analgesic. The term “resensi cally acceptable salt and/or solvate thereof is administered tizing the patient' is used herein to refer to reducing, reliev after administration of the analgesic, for example one, two, ing, attenuating, and/or reversing tolerance to the analgesic. three, four, eight, ten, twelve, 24 hours or more after admin In one aspect, the resensitized patient obtains therapeutic istration of the analgesic. In one embodiment, one dose of effect from a lower dose of the opioid analgesic than before ibogaine, ibogaine derivative, orpharmaceutically acceptable US 2015/025811 1 A1 Sep. 17, 2015

salt and/or solvate thereof is administered. In one embodi course, vary. It is also to be understood that the terminology ment, two or more doses of ibogaine, ibogaine derivative, or used herein is for the purpose of describing particular pharmaceutically acceptable salt and/or Solvate thereof are embodiments only, and is not intended to be limiting, since administered. In one embodiment, the opioid analgesic is the scope of this invention will be limited only by the interrupted for a period of time while ibogaine, ibogaine appended claims. derivative, orpharmaceutically acceptable salt and/or Solvate 0017. The detailed description of the invention is divided thereof is administered. In one embodiment, a non-opioid into various sections only for the reader's convenience and analgesic is administered while the opioid analgesic is inter disclosure found in any section may be combined with that in rupted. In one embodiment, ibogaine, ibogaine derivative, or another section. Unless defined otherwise, all technical and pharmaceutically acceptable Salt and/or Solvate thereofacts Scientific terms used herein have the same meaning as com as an analgesic. In one embodiment, the opioid analgesic is monly understood by one of ordinary skill in the art to which not interrupted during ibogaine treatment. this invention belongs. 0013. In some embodiments, the therapeutic dose of 0018. It must be noted that as used herein and in the ibogaine, ibogaine derivative, orpharmaceutically acceptable appended claims, the singular forms “a”, “an', and “the salt and/or solvate thereof administered to the patient is suf include plural referents unless the context clearly dictates ficient to provide an average serum concentration of about 50 otherwise. Thus, for example, reference to “a compound ng/mL to about 850 ng/mL (area under the curve/24 hours), or includes a plurality of compounds. any subrange or subvalue there between. In a preferred embodiment, the dose of ibogaine or pharmaceutically I. DEFINITIONS acceptable salt and/or solvate thereof administered to the 0019. Unless defined otherwise, all technical and scien patient provides an average serum concentration of about 50 tific terms used herein have the same meaning as commonly ng/mL to about 400 ng/mL. understood by one of ordinary skill in the art to which this 0014. In some embodiments, the dose of ibogaine, invention belongs. As used herein the following terms have ibogaine derivative, or pharmaceutically acceptable salt and/ the following meanings. or Solvate thereof that provides an average serum concentra 0020. The term “about when used before a numerical tion of about 50 ng/mL to about 850 ng/mL is administered as designation, e.g., temperature, time, amount, concentration, a single dose. In some embodiments, the dose of ibogaine, and Such other, including a range, indicates approximations ibogaine derivative, or pharmaceutically acceptable salt and/ which may vary by (+) or (-) 10%, 5% or 1%. or solvate thereof that provides an average serum concentra 0021 Administration” refers to introducing an agent into tion of about 50 ng/mL to about 850 ng/mL is administered as a patient. Typically, an effective amount is administered, multiple doses. In some embodiments, the aggregate dose of which amount can be determined by the treating physician or ibogaine, ibogaine derivative, orpharmaceutically acceptable the like. Any route of administration, Such as oral, topical, salt and/or Solvate thereof is from greater than about 1 mg/kg Subcutaneous, peritoneal, intra-arterial, inhalation, vaginal, to about 8 mg/kg. In a preferred embodiment, the aggregate rectal, nasal, introduction into the cerebrospinal fluid, or dose of ibogaine, ibogaine derivative, or pharmaceutically instillation into body compartments can be used. The agent acceptable salt and/or solvate thereof is from greater than may be administered by direct blood stream delivery, e.g. about 1 mg/kg to about 4 mg/kg. In another preferred embodi Sublingual, intranasal, or intrapulmonary administration. ment, the aggregate dose of ibogaine, ibogaine derivative, or 0022. The related terms and phrases “administering and pharmaceutically acceptable salt and/or Solvate thereof is “administration of, when used in connection with a com from greater than about 1 mg/kg to 3 mg/kg. pound or pharmaceutical composition (and grammatical 0.015. In some embodiments, the serum concentration is equivalents) refer both to direct administration, which may be Sufficient to modulate said tolerance while maintaining a QT administration to a patient by a medical professional or by interval of less than 500 milliseconds (ms) during said treat self-administration by the patient, and/or to indirect admin ment. In some embodiments, the therapeutic dose of istration, which may be the act of prescribing a drug. For ibogaine, ibogaine derivative, orpharmaceutically acceptable example, a physician who instructs a patient to self-adminis salt and/or solvate thereof provides prolongation of the QT ter a drug and/or provides a patient with a prescription for a interval of less than 80 ms. In one embodiment, the dose of drug is administering the drug to the patient. ibogaine, ibogaine derivative, orpharmaceutically acceptable 0023 “Periodic administration” or “periodically adminis salt and/or solvate thereof provides prolongation of the QT tering refers to multiple treatments that occur on a daily, interval of less than 50 ms. In some embodiments, the dose of weekly, or monthly basis. Periodic administration may also ibogaine, ibogaine derivative, orpharmaceutically acceptable refer to administration of ibogaine or salt and/or Solvate salt and/or solvate thereof provides prolongation of the QT thereof one, two, three, or more times per day. Administration interval of less than 30 ms. In a preferred embodiment, the may be via transdermal patch, gum, lozenge, Sublingual tab dose of ibogaine, ibogaine derivative, or pharmaceutically let, intranasal, intrapulmonary, oral administration, or other acceptable salt and/or Solvate thereof provides prolongation administration. of the QT interval of less than 20 ms. In one embodiment, the 0024 “Comprising or “comprises” is intended to mean patient is tested to determine QT interval and/or risk of pro that the compositions and methods include the recited ele longation before treatment with ibogaine, and if clinician ments, but not excluding others. “Consisting essentially of determines that the QT prolongation would be unacceptable when used to define compositions and methods, shall mean risk, ibogaine therapy will be contraindicated. excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition con DETAILED DESCRIPTION sisting essentially of the elements as defined herein would not 0016. It is to be understood that this invention is not lim exclude other materials or steps that do not materially affect ited to particular embodiments described, as such may, of the basic and novel characteristic(s) of the claimed invention. US 2015/025811 1 A1 Sep. 17, 2015

“Consisting of shall mean excluding more than trace ele cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, NRC ments of other ingredients and Substantial method steps. (=NR)N(R), halo, hydroxy, hydroxyamino, Embodiments defined by each of these transition terms are alkoxyamino, NRNR'R'', heteroaryl, heteroaryloxy, within the scope of this invention. heteroarylthio, heterocyclic, heterocyclyloxy, heterocy 0025. As used herein, N is a single bond or a double bond. clylthio, nitro, spirocycloalkyl, SOH, - OS(O) R', 0026. As used herein, the term “alkyl refers to monova —S(O) R', —C(S) R', thiocyanate, thiol, and alky lent saturated aliphatic hydrocarbyl groups having from 1 to lthio; each R" is independently selected from the group con 12 carbon atoms, 1 to 10 carbon atoms, preferably 1 to 6 sisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and carbon atoms, and more preferably 1 to 3 carbon atoms. This heterocycle, or two R' groups attached to a common atom term includes, by way of example, linear and branched hydro are optionally joined together with the atom bound thereto to carbyl groups such as methyl (CH ), ethyl (CHCH ), form a heterocycle; and each R' is independently selected n-propyl (CHCH2CH2—), isopropyl ((CH3)2CH ), n-bu from the group consisting of alkyl, cycloalkyl, aryl, het tyl (CHCHCHCH ), isobutyl ((CH) CHCH ), sec eroaryl, and heterocycle. butyl ((CH)(CH-CH2)CH ), t-butyl ((CH)C ), n-pentyl 0032 “Cyano” refers to the group –CN. (CHCH2CH2CHCH ), and neopentyl ((CH)CCH ). 0033 “Cycloalkyl refers to cyclic alkyl groups of from 3 The term “C, alkyl” refers to an alkyl group having x carbon to 10 or 3 to 8 carbon atoms having single or multiple cyclic atoms, wherein X is an integer, for example, C refers to an rings including fused, bridged, and spiro ring systems. One or alkyl group having 3 carbon atoms. more of the rings can be aryl, heteroaryl, or heterocyclic 0027 “Substituted alkyl refers to an alkyl group having provided that the point of attachment is through the non from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 aromatic, non-heterocyclic ring carbocyclic ring. Examples Substituents selected from the group consisting of alkoxy, of Suitable cycloalkyl groups include, for instance, adaman tyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. Other examples of cycloalkyl groups include bicycle 2.2.2. 0028 R20 C(O)O NROR2, C(O)NR20R2, octanyl, norbornyl, and Spirobicyclo groups such as spiro4. C(S)NR20R2, NRC(O)NR20R2, NR2C(s) 5dec-8-yl. NR'R'', O C(O)NR'R'', S(O)NR'R'', O S 0034) “Substituted cycloalkyl refers to a cycloalkyl (O)NR20R2, NR20 S(O)NR20R2, C( NR20) group having from 1 to 5 or preferably 1 to 3 substituents NR'R'', aryl, aryloxy, arylthio, azido, carboxyl, -C(O) selected from the group consisting of oxo, thione, alkyl, Sub O R', NRO C(O)O R, O C(O)O R', stituted alkyl, alkoxy, C(O) R', NRC(O)R. R. cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio, NRC C(O)O NROR2, C(O)NR'R'', C(S)NR'R'', (=NR)N(R), halo, hydroxy, hydroxyamino, NRC(O)NR2R30, NROC(S)NR2R39, O C(O) alkoxyamino, NRNR'R'', heteroaryl, heteroaryloxy, NR20R20. S(O)NR'R'', O S(O)NR'R'', heteroarylthio, heterocyclic, heterocyclyloxy, heterocy NR20 S(O)NR'R2, C(=NR2)NR'R'', aryl, ary clylthio, nitro, Spirocycloalkyl, loxy, arylthio, azido, carboxyl, -C(O)O R', NR' C SOH, -OS(O) R', -S(O). R', C(S) R', thio (O)O R', O C(O)O R', cyano, cycloalkyl, cyanate, thiol, and alkylthio; each R' is independently cycloalkyloxy, cycloalkylthio, NRC(=NR)N(R'), selected from the group consisting of hydrogen, alkyl, halo, hydroxy, hydroxyamino, alkoxyamino, cycloalkyl, aryl, heteroaryl, and heterocycle, or two R' - NRNR'R'', heteroaryl, heteroaryloxy, heteroarylthio, groups attached to a common atom are optionally joined heterocyclic, heterocyclyloxy, heterocyclylthio, nitro, Spiro together with the atom bound thereto to form a heterocycle: cycloalkyl, and each R is independently selected from the group con SOH, -OS(O) R', S(O). R', C(S) R', thio sisting of alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle. cyanate, thiol, and alkylthio; each R" is independently 0029 "Alkoxy' refers to the group —O-alkyl wherein selected from the group consisting of hydrogen, alkyl, alkyl is defined herein. Alkoxy includes, by way of example, cycloalkyl, aryl, heteroaryl, and heterocycle, or two R' methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, groups attached to a common atom are optionally joined sec-butoxy, and n-pentoxy. together with the atom bound thereto to form a heterocycle: 0030 "Aryl or 'Ar' refers to a monovalent aromatic car and each R is independently selected from the group con bocyclic group of from 6 to 14 carbon atoms having a single sisting of alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle. ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl 0035) “Halo' or “halogen” refers to fluoro, chloro, bromo or anthryl) which condensed rings may or may not be aro and iodo and preferably is fluoro or chloro. matic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)- 0036 “Haloalkyl refers to alkyl groups substituted with 1 one-7-yl, and the like) provided that the point of attachment is to 5, 1 to 3, or 1 to 2 halo groups, wherein alkyl and halo are at an aromatic carbon atom. Preferred aryl groups include as defined herein. phenyl and naphthyl. 0037 “Heteroaryl” refers to an aromatic group of from 5 0031 “Substituted aryl” refers to aryl groups which are to 14 ring atoms, including from 1 to 10 carbon atoms and 1 substituted with 1 to 5, preferably 1 to 3, or more preferably to 4 heteroatoms selected from the group consisting of oxy 1 to 2 substituents selected from the group consisting of alkyl, gen, nitrogen and Sulfur. In some embodiments, heteroaryl substituted alkyl, alkoxy, C(O) R', NRC(O)R’, comprises 5, 6, or 7 ring atoms, including 1 to 4 heteroatoms. R20 C(O)O NROR2, C(O)NR'R'', C(S) Such heteroaryl groups can have a single ring (e.g., pyridyl, NR20R20, NR20C(O)NR20R20, NR20C(S)NR20R20. pyridinyl or furyl) or multiple condensed rings (e.g., indoliz O C(O)NR'R'', S(O)NR'R'', O S(O) inyl or benzothienyl) wherein the condensed rings may or NR20R2, NRO S(O)NR'R'', C(—NR) may not be aromatic and/or contain a heteroatom provided NR'R'', aryl, aryloxy, arylthio, azido, carboxyl, -C(O) that the point of attachment is through an atom of the aromatic O R', NR C(O)O R, O C(O)C R', heteroaryl group. In one embodiment, the nitrogen and/or the US 2015/025811 1 A1 Sep. 17, 2015

Sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N->O), sulfinyl, and/or sulfonyl moieties. Preferred heteroaryls include pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl. 0038 “Substituted heteroaryl” refers to heteroaryl groups that are substituted with from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group con I0047 R is C-C alkyl, benzyl, substituted C-C alkyl, sisting of the same group of Substituents defined for Substi YH, YR, YC(O)R, C(O)YR, C(O)NHC(O)NHR, tuted aryl. C(O)NR'R'', NH, NHR, NRR, NHC(O)R, O(CH.) 0039) “Heterocycle” or “heterocyclic” or “heterocy O(CH)O(CH.), CH, or NRC(O)R’. cloalkyl or "heterocyclyl refers to a saturated or partially 0.048 R is C-C alkyl or (CHCHO),CH: saturated, but not aromatic, group having from 3 to 14 ring 0049 R,R,R,R,R,R, and R'' are independently atoms, including from 1 to 10 ring carbonatoms and from 1 to alkyl or substituted alkyl: 4 ring heteroatoms selected from the group consisting of 0050 R'' is H, alkyl, or substituted alkyl: nitrogen, Sulfur, or oxygen. In some embodiments, heteroaryl 0051) R' is H, OR', alkyl, or substituted alkyl: comprises 3, 4, 5, 6 or 7 ring atoms, including 1 to 4 heteroa 0.052 X is O or NH; toms. Heterocycle encompasses single ring or multiple con 0053 Y is O or S; densed rings, including fused bridged and spiro ring systems. 0.054 m is an integer selected from 0-8; Infused ring systems, one or more the rings can be cycloalkyl, 0.055 each of n, p and q is 1, 2 or 3; and aryl, or heteroaryl provided that the point of attachment is 0056 r is 0, 1 or 2. through the non-aromatic heterocyclic ring. In one embodi 0057. In some embodiments, the ibogaine or ibogaine ment, the nitrogen and/or Sulfur atom(s) of the heterocyclic derivative is represented by Formula II: group are optionally oxidized to provide for the N-oxide, Sulfinyl, and/or Sulfonyl moieties.

0040 “Substituted heterocyclic” or “substituted heterocy II cloalkyl or “substituted heterocyclyl refers to heterocyclyl groups that are substituted with from 1 to 5 or preferably 1 to 3 of the same substituents as defined for substituted cycloalkyl. 0041) “Ibogaine” refers to the compound:

or a pharmaceutically acceptable salt and/or Solvate thereof, wherein 1. N 0.058 R is hydrogen or C-C alkoxy, 0059) R' is hydrogen, C-C alkyl, C-C alkoxy, (CH) N H OC(O)alkyl, (CH), OH, (CH), Oalkyl, (CH)O (CH)O(CH.) O(CH), CH, or CH, Y CH, where each of m, p and q is 1, 2 or 3; and r is 0, 1 or 2,Y is O or 0042. It should be understood that where “ibogaine' is NH, and mentioned herein, one more polymorphs of ibogaine can be 0060 R is H, (CH),OH,COOH, or COOR, where R' utilized and are contemplated. Ibogaine is isolated from Tab is C-C alkyl or (CH2CH2O), CH, where n is 1, 2, or 3. ernanth iboga, a shrub of West Africa. Ibogaine can also be 0061. In one embodiment, R is methoxy. In one embodi synthesized using known methods. See, e.g., Bichi, et al. ment, R' is ethyl. In one embodiment, R' is methoxy. In one (1966), J. Am. Chem Society, 88(13), 3099-3109. embodiment, R' is CH Y CH where Y is O. In one 0043. In some embodiments, the ibogaine or ibogaine embodiment, R is CH Y CH where Y is NH. In one derivative is represented by Formula I: embodiment, R is hydrogen. In one embodiment, In one embodiment, R is COOR and R is methyl. In one embodi ment, n=1. In a preferred embodiment, R. RandR are all not

hydrogen. In one embodiment, when R is methoxy and R' is hydrogen, then R is COOH or COOR". In another embodi ment, when R is methoxy and R' is hydrogen, then X is COOR where R is (CHCHO)CH. 10062) In one embodiment, R' is hydrogen. I0063. In one embodiment, R' is H. In one embodiment, R' is C-C alkyl, such as ethyl. In one embodiment, R' is CHCH-OH. In one embodiment, R is CHCHOCH. In one embodiment, R' is CHCHOCH.Ph. In one embodi ment, R' is CHCHOC(O)alkyl. In one embodiment, R' is or a pharmaceutically acceptable salt and/or Solvate thereof, CHCHO(CH)O(CH)O(CH2)CHs. wherein 0064. In one embodiment, R is CH-OH and CH(OH)R. 0044), R is H, halo, C-C, alkyl, Substituted C-C alkyl, In one embodiment, R is CHOR. In one embodiment, R is OR, NH, NHR'9, NR'R'', NHC(O)R, or NRC COR. In one embodiment, R is C(O)NH, C(O)NHR, or (O)R'': C(O)NR'R''. In one embodiment, R is C(O)NHNH2, C(O) I0045 R' is H. C-C alkyl, substituted C-C alkyl, NHNHR, C(O)NRNHC(O)NHNRR, C(O)NHNHR, C-C alkoxy, CH, X-CH, or (CH), R: or C(O)NRNR'R''. In one embodiment, R is C(O)NHNH US 2015/025811 1 A1 Sep. 17, 2015

(C(O)R), C(O)NHNR(C(O)R), C(O)NRNHC(O)R), or 0076. In one embodiment, the ibogaine derivative is C(O)NRNR(C(O)R7). In one embodiment, R is C(O)R. selected from the group consisting of coronaridine, iboga 0065. In the various method, formulation and kit aspects mine, voacangine, 18-methoxycoronaridine, 2-Methoxy and embodiments, in one embodiment a compound utilized ethyl-18-methoxycoronaridinate, and 18-Methylaminocoro herein is represented by, oribogaine as used herein is replaced naridine. by, a compound Formula I: 0077. In one embodiment, the ibogaine derivative is selected from the group consisting of 16-hydroxymethyl-18 hydroxyibogaline, 16-hydroxymethyl-18-methoxyiboga line, 16-ethoxycarbonyl-18-hydroxyibogaline laurate, and 16-ethoxycarbonyl-18-hydroxyibogaline methoxyethoxym ethyl ether. 0078. In one embodiment, the compound is of Formula IA:

IA wherein 0066 R is hydrogen or C-C-alkoxy, I0067) R' is hydrogen, C-C-alkyl, C-C alkoxy, or CH Y CH, where Y is O or NH, and 0068 X is H, COOH, or COOR, where R is C-C, alkyl or (CHCHO), CH, where n=1 to 3. 0069. In another embodiment, ibogaine or a pharmaceuti cally acceptable salt and/or solvate thereof is utilized. In wherein another embodiment, ibogaine or a pharmaceutically accept able salt and/or solvate thereof is utilized. In another embodi 0079 R is hydrogen or C-C-alkoxy, ment, the ibogaine, ibogaine derivative, is chosen from the 0080) R' is hydrogen, C-C-alkyl, C-C alkoxy, or group consisting of ibogaine, coronaridine, ibogamine, Voa CH Y CH where Y is O or NH, and cangine, 18-methoxycoronaridine, 2-methoxyethyl-18 0081 X is H, COOH, or COOR, where R is C-C, methoxycoronaridinate, 18-methylaminocoronaridine or a alkyl or (CHCHO), CH, where n=1 to 3. pharmaceutically acceptable salt and/or Solvate thereof. I0082 In another embodiment, the ibogaine derivative is 0070. In another embodiment, the compound utilized represented by Formula II: herein is chosen from the group consisting of ibogaine, coro naridine, ibogamine, voacangine, 18-methoxycoronaridine,

2-methoxyethyl-18-methoxycoronaridinate, 18-methylami II nocoronaridine and a pharmaceutically acceptable salt and/or Solvate. 0071. In another embodiment, the compound utilized herein is selected from the group consisting of 16-hydroxym ethyl-18-hydroxyibogaline, 16-hydroxymethyl-18-meth oxyibogaline, 16-ethoxycarbonyl-18-hydroxyibogaline lau rate, and 16-ethoxycarbonyl-18-hydroxyibogaline methoxyethoxymethyl ether and a pharmaceutically accept able salt and/or solvate thereof. or a pharmaceutically acceptable salt and/or Solvate thereof, 0072. In one embodiment, the ibogaine derivative is rep wherein resented by Formula II: 0.083 R is OCH: 0084) R' is CHCH; and I0085) R is COOR, where R is (CHCHO), CH, II where n is 1. I0086. When replacing ibogaine, the compounds of for mula I, II, and subformulas thereofas utilized herein exclude ibogaine. 0087 In a preferred embodiment, the compound utilized herein is: or a pharmaceutically acceptable salt and/or Solvate thereof, wherein 0073 R is hydrogen or C-C alkoxy; 10074) R' is hydrogen, C-C alkyl, C-C alkoxy, (CH.) OC(O)alkyl, (CH), OH, (CH), Oalkyl, (CH)O (CH)O(CH2)(O(CH2), CH, or CH Y CH, where N each of m, p and q is 1, 2 or 3; and r is 0, 1 or 2,Y is O or NH; and (0075 Riis H. (CH),OH,COOH, or COOR, where R' a pharmaceutically acceptable salt thereof, or a Solvate of is C-C alkyl or (CH2CH2O), CH, where n is 1, 2, or 3. each thereof. US 2015/025811 1 A1 Sep. 17, 2015

0088. In some embodiments, the ibogaine or ibogaine derivative is selected from:

Name Structure coronaridine N

N COCH3 18-hydroxycoronaridine N OH

N COCH3 18-methoxycoronaridine N OCH

N COCH 18-benzyloxycoronaridine

N O

N COCH 18-hydroxycoronaridine (CH2)10CH3 laurate N O

N COCH3 18-hydroxycoronaridine / methoxyethoxymethyl ether OU/ O

N COCH3 18-hydroxycoronaridine acetate N sk

N COCH voacangine N

O 1. N N COCH3 US 2015/025811 1 A1 Sep. 17, 2015

-continued

Name Structure 18-hydroxy voacangine OH

N COCH3 18-methoxy voacangine OCH

N COCH 18-benzyloxy voacangine

N COCH3 18-hydroxy voacangine (CH2)(CH3 laurate

N COCH 18-hydroxy voacangine acetate

N COCH3 18-hydroxy voacangine methoxyethoxymethyl ether

N COCH3 conopharyngine

N COCH 18-hydroxyconopharyngine OH

N COCH US 2015/025811 1 A1 Sep. 17, 2015

-continued

Name Structure 18-methoxyconopharyngine N OCH O 1. N No N COCH

18-benzyloxyconopharyngine

N O O 1. N No N COCH

18-hydroxyconopharyngine N O (CH2)(CH3CH) CH laurate O 1. N O No N COCH 18-hydroxyconopharyngine acetate

No N COCH

18-hydroxyconopharyngine methoxyethoxymethyl ether N O-N/O / O 1. N No N COCH3 ibogamine N

N H 16-ethoxycarbonyl-18 hydroxyibogamine N OH

N CO2CH2CH 16-hydroxymethyl-18 hydroxyibogamine N OH

N HOH US 2015/025811 1 A1 Sep. 17, 2015

-continued

Name Structure 16-ethoxycarbonyl-18 methoxyibogamine N OCH

N COCH2CH3 16-hydroxymethyl-18 methoxyibogamine N OCH

N CH2OH 16-ethoxycarbonyl-18 benzyloxyibogamine

N O

N COCH2CH3

16-ethoxycarbonyl-18 N O (CH2)10CH3CH) CH hydroxyibogamine laurate N O N COCH2CH3

16-ethoxycarbonyl-18 hydroxyibogamine acetate N -( N O N COCH2CH3 16-ethoxycarbonyl-18 hydroxyibogamine methoxyethoxymethyl ether N O-N/OU/

N COCH2CH3 ibogaine N O

N H

16-ethoxycarbonyl-18 hydroxyibogaine N OH O 1. N N COCH2CH3 US 2015/025811 1 A1 Sep. 17, 2015

-continued

Name Structure 16-hydroxymethyl-18 hydroxyibogaine N OH O 1. N N (HOH 16-ethoxycarbonyl-18 methoxyibogaine N O-N- O 1. N N CO2CH2CH 16-hydroxymethyl-18 methoxyibogaine N OCH O 1. N N HOH 16-ethoxycarbonyl-18 benzyloxyibogaine

N O O 1. N N COCH2CH3

16-ethoxycarbonyl-18 (CH2)(CH3 hydroxyibogaine laurate N O O

N CO2CH2CH

16-ethoxycarbonyl-18 hydroxyibogaine acetate

N COCH2CH3

16-ethoxycarbonyl-18 hydroxyibogaine methoxyethoxymethyl ether N O-N/OU/ O 1. N N COCH2CH3 ibogaline N US 2015/025811 1 A1 Sep. 17, 2015 11

-continued

Name Structure 16-ethoxycarbonyl-18 hydroxyibogaline N OH O 1. N No N CO2CH2CH 16-hydroxymethyl-18 hydroxyibogaline N OH O 1. N No N CH2OH 16-ethoxycarbonyl-18 methoxyibogaline N OCH O 1. N

No NH COCH2CH3 16-hydroxymethyl-18 methoxyibogaline N OCH O 1. N No N CH2OH 16-ethoxycarbonyl-18 benzyloxyibogaline

N O O 1. N

No NH COCH2CH3

16-ethoxycarbonyl-18 N O (CH2)10CH3CH) CH hydroxyibogaline laurate O 1. N O

No NH COCH2CH3 16-ethoxycarbonyl-18 hydroxyibogaline acetate N O - No N COCH2CH3 16-ethoxycarbonyl-18 hydroxyibogaline O-4 methoxyethoxymethyl ether N O-N/ O 1. N No N CO2CH2CH and pharmaceutically acceptable salts and/or Solvates thereof. US 2015/025811 1 A1 Sep. 17, 2015 12

0089. In one embodiment, the ibogaine derivative is: used. Examples of Such acids include, without limitation, those described below as “pharmaceutically acceptable salts' and the like. 0091 "Pharmaceutically acceptable composition” refers to a composition that is suitable for administration to a human. Such compositions include various excipients, dilu ents, carriers, and Such other inactive agents well known to the skilled artisan. N 0092 “Pharmaceutically acceptable salt” refers to phar O maceutically acceptable salts, including pharmaceutically acceptable partial salts, of a compound, which salts are (coronaridine) derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, N hydrochloric acid, hydrobromic acid, phosphoric acid, Sulfu ric acid, methane Sulfonic acid, phosphorous acid, nitric acid, N s perchloric acid, acetic acid, tartaric acid, lactic acid, Succinic N acid, citric acid, malic acid, maleic acid, aconitic acid, Sali H cylic acid, thalic acid, embonic acid, enanthic acid, oxalic (ibogamine) acid and the like, and when the molecule contains an acidic functionality, include, by way of example only, Sodium, potassium, calcium, magnesium, ammonium, tetraalkylam monium, and the like. N s 0093. A “pharmaceutically acceptable solvate or hydrate' of a compound of the invention means a Solvate or hydrate N H complex that is pharmaceutically acceptable and that pos O sesses the desired pharmacological activity of the parent com pound, and includes, but is not limited to, complexes of a (voacangine) compound of the invention with one or more solvent or water molecules, or 1 to about 100, or 1 to about 10, or one to about N O 2, 3 or 4, solvent or water molecules. 0094. As used herein the term solvate is taken to mean that a solid-form of a compound that crystallizes with one or more molecules of Solvent trapped inside. A few examples of Sol N H vents that can be used to create Solvates, such as pharmaceu O tically acceptable Solvates, include, but are certainly not lim ited to, water, methanol, ethanol, isopropanol, butanol, (18-methoxycoronaridine, 18-MC) C1-C6 alcohols in general (and optionally substituted), tet rahydrofuran, acetone, ethylene glycol, propylene glycol, N ON acetic acid, formic acid, water, and solvent mixtures thereof. s O Other such biocompatible solvents which may aid in making N a pharmaceutically acceptable solvate are well known in the art and applicable to the present invention. Additionally, vari N H ous organic and inorganic acids and bases can be added or O O even used alone as the solvent to create a desired solvate. Such acids and bases are known in the art. When the solvent is N-N water, the solvate can be referred to as a hydrate. Further, by (2-Methoxyethyl-18-methoxycoronaridinate, ME-18-MC) being left in the atmosphere or recrystallized, the compounds of the present invention may absorb moisture, may include N NN one or more molecules of water in the formed crystal, and thus become a hydrate. Even when such hydrates are formed, they N are included in the term "solvate”. Solvate also is meant to include such compositions where another compound or com plex co-crystallizes with the compound of interest. O O (0095 “Therapeutically effective amount” or “therapeutic amount refers to an amount of a drug or an agent that, when (18-Methylaminocoronaridine, 18-MAC) administered to a patient Suffering from a condition, will have the intended therapeutic effect, e.g., alleviation, amelioration, palliation or elimination of one or more manifestations of the 0090 This invention is not limited to any particular chemi condition in the patient. The therapeutically effective amount cal form of ibogaine oribogaine derivative, and the drug may will vary depending upon the patient and the condition being be given to patients either as a free base, Solvate, or as a treated, the weight and age of the subject, the severity of the pharmaceutically acceptable acid addition salt. In the latter condition, the salt, Solvate, or derivative of the active drug case, the hydrochloride salt is generally preferred, but other portion chosen, the particular composition or excipient cho salts derived from organic or inorganic acids may also be sen, the dosing regimen to be followed, timing of administra US 2015/025811 1 A1 Sep. 17, 2015

tion, the manner of administration and the like, all of which itching. It may be continuous and/or episodic. Neuropathic can be determined readily by one of ordinary skill in the art. pain is difficult to treat, but opioids, including, without limi The full therapeutic effect does not necessarily occur by tation, methadone, tramadol, tapentadol, oxycodone, metha administration of one dose, and may occur only after admin done, morphine, levorphanol, and the like. Causes of neuro istration of a series of doses. Thus, a therapeutically effective pathic pain include, without limitation, alcoholism; amount may be administered in one or more administrations. amputation; back, leg, and hip problems; chemotherapy; dia For example, and without limitation, a therapeutically effec betes; facial nerve problems; HIV/AIDS; multiple sclerosis: tive amount of ibogaine, in the context of modulating opioid shingles; spine Surgery; trigeminal neuralgia; fibromyalgia; analgesic tolerance, refers to an amount of ibogaine that and the like. In some cases, the cause of neuropathic pain may resensitizes the patient to the opioid analgesic therapy. be unclear or unknown. 0096. A “therapeutic level of a drug is an amount of 0100 Addictive' refers to a compound that, when admin ibogaine, ibogaine derivative, or pharmaceutical salt and/or istered to a mammal over a period of time, creates depen solvate thereof that is sufficient to modulate tolerance to an dency in the mammal to that compound. The dependence can opioid analgesic, but not high enough to pose any significant be physiological and/or psychological. Atherapeutic effect of risk to the patient. Therapeutic levels of drugs can be deter an addictive compound on a mammal may decrease with mined by tests that measure the actual concentration of the prolonged administration of the addictive compound, which compound in the blood of the patient. This concentration is is a non-limiting example of a physiological dependence. referred to as the "serum concentration’. Where the serum When administered to a mammal, an addictive compound concentration of ibogaine is mentioned, it is to be understood may also create a craving in the mammal for more of it, which that the term “libogaine' encompasses any form of ibogaine, is a non-limiting example of a psychological dependence. including derivatives thereof. Examples of addictive compounds include, without limita 0097. “Treatment,” “treating,” and “treat” are defined as tion, addictive opioids, and the like. acting upon a disease, disorder, or condition with an agent to 0101 “Opioid refers to a natural product or derivative reduce or ameliorate harmful or any other undesired effects of thereof containing a basic nitrogen atom, typically as part of the disease, disorder, or condition and/or its symptoms. a cyclic ring structure and less commonly as an acyclic moi “Treatment, as used herein, covers the treatment of a human ety, and synthetic derivatives thereof. Opioids include com patient, and includes: (a) reducing the risk of occurrence of pounds extracted from poppy pods and their semi-synthetic the condition in a patient determined to be predisposed to the counterparts which bind to the opiate receptors. Examples of condition but not yet diagnosed as having the condition, (b) opioids include, without limitation, buprenorphine, codeine, impeding the development of the condition, and/or (c) reliev heroine, hydrocodone, oxycodone, morphine, thebaine, and ing the condition, i.e., causing regression of the condition their derivatives, which will be well known to the skilled and/or relieving one or more symptoms of the condition. artisan. “Treating or “treatment of a condition or patient refers to 0102 “Analgesic' and “analgesic agent” refer to a com taking steps to obtain beneficial or desired results, including pound that is capable of inhibiting and/or reducing pain in clinical results such as the reduction of symptoms. For pur mammals. Pain may be inhibited and/or reduced in the mam poses of this invention, beneficial or desired clinical results mal by the binding of the opioid analgesic agent to the mu include, but are not limited to modulating, reducing, attenu receptor. When analgesia is effected through the mu receptor, ating, relieving or reversing tolerance to an opioid analgesic the analgesic agent is referred to as a mu receptor agonist. compound. Certain analgesic agents are capable of inhibiting nociceptive 0098 “Nociceptive pain” refers to pain that is sensed by and/or neuropathic pain including, by way of example, mor nociceptors, which are the nerves that sense and respond to phine, codeine, hydromorphone, oxycodone, hydrocodone, parts of the body suffering from a damage. The nociceptors buprenorphin, and the like. can signal tissue irritation, impending injury, or actual injury. 0103) As used herein, the term “patient” refers to mam When activated, they transmit pain signals (via the peripheral mals and includes humans and non-human mammals. nerves as well as the spinal cord) to the brain. Nociceptive 0104. As used herein, the term “QT interval” refers to the pain is typically well localized, constant, and often has an measure of the time between the start of the Q wave and the aching or throbbing quality. A Subtype of nociceptive pain end of the T wave in the electrical cycle of the heart. Prolon includes visceral pain and involves the internal organs. Vis gation of the QT interval refers to an increase in the QT ceral paintends to be episodic and poorly localized. Nocice interval. ptive pain may be time limited; when the tissue damage heals, 0105. The term “tolerance' as used herein refers to the the pain typically resolves. However, nociceptive pain related psychological and/or physiologic process wherein the patient to arthritis or cancer may not be time limited. Nociceptive adjusts to the frequent presence of a Substance Such that a pain tends to respond to treatment with opiate analgesics, higher dose of the Substance is required to achieve the same Such as, for example, buprenorphin, codeine, hydrocodone, effect. Tolerance may develop at different times for different oxycodone, morphine, and the like. Examples of nociceptive effects of the same drug (e.g., analgesic effect versus side pain include, without limitation, pains from sprains, bone effects). The mechanisms of tolerance are not entirely under fractures, burns, bumps, bruises, inflammatory pain from an stood, but they may include receptor down-regulation or infection or arthritic disorder, pains from obstructions, cancer desensitization, inhibitory pathway up-regulation, increased pain, and myofascial pain related to abnormal muscle metabolism, and/or changes in receptor processing (e.g., StreSSes. phosphorylation). 0099 “Neuropathic pain” refers to chronic pain, often due 0106 A“pharmaceutically acceptable solvate or hydrate' to tissue injury. Neuropathic pain is generally caused by of a compound of the invention means a Solvate or hydrate injury or damage to nerve fibers. It may include burning or complex that is pharmaceutically acceptable and that pos coldness, “pins and needles' sensations, numbness and/or sesses the desired pharmacological activity of the parent com US 2015/025811 1 A1 Sep. 17, 2015 pound, and includes, but is not limited to, complexes of a about 50 ng/mL to about 500 ng/mL, or about 60 ng/mL to compound of the invention with one or more solvent or water about 500 ng/mL. In one embodiment, the average serum molecules, or 1 to about 100, or 1 to about 10, or one to about concentration of ibogaine is from about 50 ng/mL to about 2, 3 or 4, solvent or water molecules. 400 ng/mL, or about 60 ng/mL to about 400 ng/mL. In one embodiment, the average serum concentration of ibogaine is II. Methods of the Invention from about 50 ng/mL to about 300 ng/mL, or about 60 ng/mL 0107 As will be apparent to the skilled artisan upon read to about 300 ng/mL. In one embodiment, the average serum ing this disclosure, the present invention provides a method concentration of ibogaine is from about 50 ng/mL to about for modulating tolerance to opioids in a patient undergoing 200 ng/mL, or about 60 ng/mL to about 200 ng/mL. In one opioid analgesic therapy, comprising administering to the embodiment, the average serum concentration of ibogaine is patient a dosage of ibogaine, ibogaine derivative, or pharma from about 50 ng/mL to about 100 ng/mL, or about 60 ng/mL ceutically acceptable salt and/or solvate thereof. to about 100 ng/mL. The ranges include both extremes as well 0108. In one aspect of this invention, patient is being as any Subranges therebetween. treated with an addictive opioid analgesic to relieve the 0112 In one embodiment, the dosage or aggregate dosage patient’s pain. The pain may be of any type and from any of ibogaine, ibogaine derivative, or pharmaceutically accept Source. In one embodiment, the patient is treated for acute able salt and/or solvate thereof is from greater than about 1 pain. In one embodiment, the patient is treated for chronic mg/kg to about 8 mg/kg body weight per day. The aggregate pain. In one embodiment, the patient is treated for nociceptive dosage is the combined dosage, for example the total amount pain. In one embodiment, the patient is treated for neuro of ibogaine, ibogaine derivative, or pharmaceutically accept pathic pain. In some embodiments, the pain is caused by able salt and/or solvate thereof administered over a 24-hour Surgery, diabetes, trigeminal neuralgia, fibromyalgia, cancer, period where Smaller amounts are administered more than central pain syndrome, tissue damage, physical injury, and once per day. In one embodiment, the dosage or aggregate the like. In some embodiments, the source of the pain is dosage of ibogaine, ibogaine derivative, or salt and/or Solvate unknown or unclear. thereof is from about 1.3 mg/kg to about 7 mg/kg body 0109. In one aspect, this invention relates to a method for weight. In one embodiment, the dosage or aggregate dosage modulating tolerance to an opioid analgesic in a patient of ibogaine, ibogaine derivative, or salt and/or Solvate thereof undergoing opioid analgesic therapy, the method comprising is from about 1.3 mg/kg to about 6 mg/kg body weight. In one interrupting or administering concurrently with said opioid embodiment, the dosage or aggregate dosage of ibogaine, analgesic anamount of ibogaine, ibogaine derivative, orphar ibogaine derivative, or salt and/or solvate thereof is from maceutically acceptable salt and/or solvate thereof that pro about 1.3 mg/kg to about 5 mg/kg body weight. In a preferred vides an average serum concentration of about 50 ng/mL to embodiment, the dosage or aggregate dosage of ibogaine, about 850 ng/mL, said concentration being sufficient resen ibogaine derivative, or salt and/or solvate thereof is from sitize the patient to the opioid as an analgesic while maintain about 1.3 mg/kg to about 4 mg/kg body weight. In one ing a QT interval of less than about 500 ms during said embodiment, the dosage or aggregate dosage of ibogaine, treatment. ibogaine derivative, or salt and/or solvate thereof is from 0110. In one aspect, this invention relates to a method for about 1.3 mg/kg to about 3 mg/kg body weight. In one modulating tolerance to an opioid analgesic in a patient embodiment, the dosage or aggregate dosage of ibogaine, undergoing opioid analgesic therapy, the method comprising ibogaine derivative, or salt and/or solvate thereof is from interrupting or administering concurrently with said opioid about 1.3 mg/kg to about 2 mg/kg body weight. In one analgesic anamount of ibogaine, ibogaine derivative, orphar embodiment, the dosage or aggregate dosage of ibogaine, maceutically acceptable salt and/or solvate thereof that pro ibogaine derivative, or salt and/or solvate thereof is from vides an average serum concentration of about 60 ng/mL to about 1.5 mg/kg to about 3 mg/kg body weight. In one about 400 ng/mL, said concentration being Sufficient to embodiment, the dosage or aggregate dosage of ibogaine, resensitize the patient to the opioid as an analgesic while ibogaine derivative, or salt and/or solvate thereof is from maintaining a QT interval of less than about 500 ms during about 1.7 mg/kg to about 3 mg/kg body weight. In one said treatment. In some embodiments, the concentration is embodiment, the dosage or aggregate dosage of ibogaine, Sufficient to resensitize the patient to the opioid as an analge ibogaine derivative, or salt and/or solvate thereof is from sic while maintaining a QT interval of less than about 470 ms about 2 mg/kg to about 4 mg/kg body weight. In one embodi during treatment. Preferably, the concentration is sufficient to ment, the dosage or aggregate dosage of ibogaine, ibogaine resensitize the patient to the opioid as an analgesic while derivative, or salt and/or solvate thereof is from about 2 mg/kg maintaining a QT interval of less than about 450 ms during to about 3 mg/kg body weight. In one embodiment, the dos treatment. In one embodiment, the concentration is sufficient age or aggregate dosage of ibogaine, ibogaine derivative, or to resensitize the patient to the opioid as an analgesic while salt and/or solvate thereof is about 2 mg/kg body weight. The maintaining a QT interval of less than about 420 ms during ranges include both extremes as well as any Subranges there treatment. between. 0111. In one embodiment, the average serum concentra 0113. In one embodiment, the dosage or aggregate dosage tion of ibogaine is from about 50 ng/mL to about 800 ng/mL of ibogaine, ibogaine derivative, or salt and/or Solvate thereof or about 60 ng/mL to about 800 ng/mL. In one embodiment, is about 8 mg/kg body weight per day. In one embodiment, the the average serum concentration of ibogaine is from about 50 dosage or aggregate dosage of ibogaine, ibogaine derivative, ng/mL to about 700 ng/mL or about 60 ng/mL to about 700 or salt and/or solvate thereof is about 7 mg/kg body weight ng/mL. In one embodiment, the average serum concentration per day. In one embodiment, the dosage or aggregate dosage of ibogaine is from about 50 ng/mL to about 600 ng/mL, or of ibogaine, ibogaine derivative, or salt and/or Solvate thereof about 60 ng/mL to about 600 ng/mL. In a preferred embodi is about 6 mg/kg body weight per day. In one embodiment, the ment, the average serum concentration of ibogaine is from dosage or aggregate dosage of ibogaine, ibogaine derivative, US 2015/025811 1 A1 Sep. 17, 2015 or salt and/or solvate thereof is about 5 mg/kg body weight form. In certain embodiments, the ibogaine is provided as per day. In one embodiment, the dosage or aggregate dosage ibogaine HCl, with dosages reported as the amount of free of ibogaine, ibogaine derivative, or salt and/or Solvate thereof base ibogaine. In some embodiments, the ibogaine HCl is is about 4 mg/kg body weight per day. In one embodiment, the provided in hard gelatin capsules containing only ibogaine dosage or aggregate dosage of ibogaine, ibogaine derivative, HCl with no excipients. or salt and/or solvate thereof is about 3 mg/kg body weight 0119 The patient may be receiving any addictive opioid per day. In one embodiment, the dosage or aggregate dosage analgesic for the treatment of pain. In a preferred embodi of ibogaine, ibogaine derivative, or salt and/or Solvate thereof ment, the opioid analgesic is selected from the group consist is about 2 mg/kg body weight per day. In one embodiment, the ing of fentanyl, hydrocodone, hydromorphone, morphine, dosage or aggregate dosage of ibogaine, ibogaine derivative, oxycodone, buprenorphine, codeine, heroin, thebaine, or salt and/or solvate thereof is about 1.7 mg/kg body weight buprenorphine, methadone, meperidine, tramadol, tapenta per day. In one embodiment, the dosage or aggregate dosage dol, levorphanol, Sufentanil, pentazocine, oxymorphone, and of ibogaine, ibogaine derivative, or salt and/or Solvate thereof derivatives of each thereof. is about 1.5 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine deriva Patient Pre-Screening and Monitoring tive, or salt and/or solvate thereof is about 1.3 mg/kg body I0120 Pre-screening of patients before treatment with weight per day. In one embodiment, the dosage or aggregate ibogaine, ibogaine derivative, orpharmaceutically acceptable dosage of ibogaine, ibogaine derivative, or salt and/or Solvate salt and/or Solvate thereof and/or monitoring of patients dur thereof is about 1 mg/kg body weight per day. ing ibogaine treatment may be required to ensure that QT 0114. In one embodiment, ibogaine is administered at an interval is not prolonged beyond a certain value. For example, amount by weight that is twice that administered for nori QT interval greater than 500 ms can be considered dangerous bogaine for treating a same or similar condition. For example, for individual patients. Pre-screening and/or monitoring may and without limitation, an administration of a dose 80 mg be necessary at high levels of ibogaine treatment. ibogaine approximates a dose of 40 mg noribogaine. 0121. In one embodiment, a patient receiving atherapeutic 0115. In one embodiment, the QT interval is not prolonged dose of ibogaine, ibogaine derivative, or pharmaceutically more than about 50 ms. In one embodiment, the QT interval acceptable salt and/or solvate thereof is monitored in a clini is not prolonged more than about 40 ms. In one embodiment, cal setting. Monitoring may be necessary to ensure the QT the QT interval is not prolonged more than about 30 ms. In interval is not prolonged to an unacceptable degree. A “clini one embodiment, the QT interval is not prolonged more than cal setting refers to an inpatient setting (e.g., inpatient clinic, about 20 ms. In one embodiment, the QT interval is not hospital, rehabilitation facility) or an outpatient setting with prolonged more than about 10 ms. frequent, regular monitoring (e.g., outpatient clinic that is 0116. In some embodiments, the patient is administered visited daily to receive dose and monitoring). Monitoring periodically, such as once, twice, three times, four times or includes monitoring of QT interval. Methods for monitoring five times daily with ibogaine, ibogaine derivative, or a phar of QT interval are well-known in the art, for example by ECG. maceutically acceptable salt and/or Solvate thereof. In some I0122. In one embodiment, a patient administered embodiments, the administration is once daily, or once every ibogaine, ibogaine derivative, orpharmaceutically acceptable second day, once every third day, three times a week, twice a salt and/or Solvate thereof is not monitored in a clinical set week, or once a week. The dosage and frequency of the ting. In one embodiment, a patient administered ibogaine, administration depends on the route of administration, dos ibogaine derivative, or pharmaceutically acceptable salt and/ age, age and body weight of the patient, condition of the or solvate thereof is monitored periodically, for example patient, opioid analgesic to which tolerance is being modu daily, weekly, monthly, or occasionally. lated, length of time of analgesic treatment, and the like, I0123. In one aspect, this invention relates to a method for without limitation. Determination of dosage and frequency modulating tolerance to an opioid analgesic in a patient Suitable for the present technology can be readily made a undergoing opioid analgesic therapy, comprising selecting a qualified clinician. patient who is prescreened to evaluate the patient's expected 0117 Ibogaine, ibogaine derivative, or a pharmaceutically tolerance for prolongation of QT interval, and administering acceptable salt and/or solvate thereof, suitable for adminis to the patient a dosage of ibogaine, ibogaine derivative, or tration in accordance with the methods provide herein, can be pharmaceutically acceptable salt and/or solvate thereof that suitable for a variety of delivery modes including, without provides an average serum concentration of about 50 ng/mL limitation, oral and transdermal delivery. Compositions Suit to about 850 ng/mL, said concentration being sufficient to able for internal, pulmonary, rectal, nasal, vaginal, lingual, resensitize the patient to the opioid as an analgesic while intravenous, intra-arterial, intramuscular, intraperitoneal, maintaining a QT interval of less than 500 ms during said intracutaneous and Subcutaneous routes may also be used. treatment. In some embodiments, the concentration is suffi Possible dosage forms include tablets, capsules, pills, pow cient to resensitize the patient to the opioid as an analgesic ders, aerosols, Suppositories, parenterals, and oral liquids, while maintaining a QT interval of less than about 470 ms including Suspensions, Solutions and emulsions. Sustained during treatment. Preferably, the concentration is sufficient to release dosage forms may also be used. All dosage forms may resensitize the patient to the opioid as an analgesic while be prepared using methods that are standard in the art (see maintaining a QT interval of less than about 450 ms during e.g., Remington’s Pharmaceutical Sciences, 16th ed., A. Oslo treatment. In one embodiment, the concentration is sufficient editor, Easton Pa. 1980). to resensitize the patient to the opioid as an analgesic while 0118. In a preferred embodiment, ibogaine, ibogaine maintaining a QT interval of less than about 420 ms during derivative, or a pharmaceutically acceptable salt and/or sol treatment. vate thereof is administered orally, which may conveniently 0.124. In one embodiment, prescreening of the patient be provided in tablet, caplet, Sublingual, liquid or capsule comprises ascertaining that ibogaine treatment will not result US 2015/025811 1 A1 Sep. 17, 2015

in a QT interval over about 500 ms. In one embodiment, tion, etc. In one embodiment, the kit of parts further com prescreening of the patient comprises ascertaining that prises instructions for dosing and/or administration of the ibogaine treatment will not result in a QT interval over about composition. 470 ms. In one embodiment, prescreening comprises ascer I0129. In some aspects, the invention is directed to a kit of taining that ibogaine treatment will not result in a QT interval parts for administration of ibogaine, ibogaine derivative, over about 450 ms. In one embodiment, prescreening com pharmaceutically acceptable Salt and/or Solvate thereof, the prises ascertaining that ibogaine treatment will not result in a kit comprising multiple delivery vehicles, wherein each QT interval over about 420 ms. In one embodiment, pre delivery vehicle contains a discrete amount of ibogaine, screening comprises determining the patient’s pre-treatment ibogaine derivative, pharmaceutically acceptable salt and/or QT interval. solvate thereof and further wherein each delivery vehicle is 0.125. As it relates to pre-screening or pre-selection of identified by the amount of ibogaine, ibogaine derivative, patients, patients may be selected based on any criteria as pharmaceutically acceptable salt and/or Solvate thereof pro determined by the skilled clinician. Such criteria may vided therein; and optionally further comprising a dosing include, by way of non-limiting example, pre-treatment QT treatment schedule in a readable medium. In some embodi interval, pre-existing cardiac conditions, risk of cardiac con ments, the dosing treatment schedule includes the amount of ditions, age, sex, general health, and the like. The following ibogaine, ibogaine derivative, pharmaceutically acceptable are examples of selection criteria for disallowing ibogaine salt and/or Solvate thereof required to achieve each average treatment or restricting dose of ibogaine administered to the serum level is provided. In some embodiments, the kit of parts patient: high QT interval before treatment (e.g., Such that includes a dosing treatment schedule that provides an attend there is a risk of the patient’s QT interval exceeding 500 ms ing clinician the ability to select a dosing regimen of ibogaine during treatment); congenital long QT syndrome; bradycar based on criteria such as, without limitation, the sex of the dia; hypokalemia or hypomagnesemia; recent acute myocar patient, mass of the patient, and the serum level that the dial infarction; uncompensated heart failure; and taking other clinician desires to achieve. In some embodiments, the dosing drugs that increase QT interval. In some embodiments, the treatment schedule further provides information correspond methods can include selecting and/or administering/provid ing to the Volume of blood in a patient based upon weight (or ing ibogaine to a patient that lacks one more of Such criteria. mass) and sex of the patient. In an embodiment, the storage medium can include an accompanying pamphlet or similar 0126. In one embodiment, this invention relates to pre written information that accompanies the unit dose form in screening a patient to determine if the patient is at risk for the kit. In an embodiment, the storage medium can include prolongation of the QT interval beyond a safe level. In one electronic, optical, or other data storage, such as a non-vola embodiment, a patient at risk for prolongation of the QT tile memory, for example, to store a digitally-encoded interval beyond a safe level is not administered ibogaine. In machine-readable representation of Such information. one embodiment, a patient at risk for prolongation of the QT I0130. The term “delivery vehicle' as used herein refers to interval beyond a safe level is administered ibogaine, any formulation that can be used for administration of ibogaine derivative, or pharmaceutically acceptable salt and/ ibogaine, ibogaine derivative, pharmaceutically acceptable or Solvate thereof at a limited dosage. In one embodiment, a salt and/or Solvate thereof to a patient. Non-limiting, exem limited dosage is a dosage of ibogaine, ibogaine derivative, or plary delivery vehicles include caplets, pills, capsules, tab pharmaceutically acceptable salt and/or solvate thereofthat is lets, powder, liquid, or any other form by which the drug can not expected to result in an unacceptable prolongation of the be administered. Delivery vehicles may be intended for patient’s QT interval. administration by oral, inhaled, injected, or any other means. 0127. In one embodiment, this invention relates to moni 0131 The term “readable medium' as used herein refers toring a patient who is administered a therapeutic dose of to a representation of data that can be read, for example, by a ibogaine, ibogaine derivative, or salt and/or Solvate thereof. In human or by a machine. Non-limiting examples of human one embodiment, the dose of ibogaine is reduced if the patient readable formats include pamphlets, inserts, or other written has one or more adverse side effects. In one embodiment, the forms. Non-limiting examples of machine-readable formats ibogaine treatment is discontinued if the patient has one or include any mechanism that provides (i.e., Stores and/or more adverse side effects. In one embodiment, the adverse transmits) information in a form readable by a machine (e.g., side effect is a QT interval that is prolonged beyond a safe a computer, tablet, and/or Smartphone). For example, a level. The determination of a safe level of prolongation is machine-readable medium includes read-only memory within the skill of a qualified clinician. (ROM); random access memory (RAM); magnetic disk stor age media; optical storage media; and flash memory devices. Kit of Parts In one embodiment, the machine-readable medium is a CD ROM. In one embodiment, the machine-readable medium is 0128. One aspect of this invention is directed to a kit of a USB drive. In one embodiment, the machine-readable parts for the modulation of tolerance to an opioid analgesic, medium is a Quick Response Code (QR Code) or other matrix wherein the kit comprises a composition comprising barcode. ibogaine, ibogaine derivative, or salt and/or Solvate thereof 0.132. In some aspects, the machine-readable medium and a means for administering the composition to a patient in comprises Software that contains information regarding dos need thereof. The means for administration to a patient can ing schedules for the unit dose form of ibogaine and option include, for example, any one or combination of ibogaine, or ally other drug information. In some embodiments, the Soft a ibogaine derivative, or a pharmaceutically acceptable salt ware may be interactive, such that the attending clinician or and/or Solvate thereof, a transdermal patch, a Syringe, a other medical professional can enter patient information. In a needle, an IV bag comprising the composition, a vial com non-limiting example, the medical professional may enter the prising the composition, an inhaler comprising the composi weight and sex of the patient to be treated, and the software US 2015/025811 1 A1 Sep. 17, 2015 program provides a recommended dosing regimen based on ibogaine, ibogaine derivative, orpharmaceutically acceptable the information entered. The amount and timing of ibogaine salt and/or Solvate thereof is sufficient to provide an average recommended to be delivered will be within the dosages that serum concentration of about 50 ng/mL to about 400 ng/mL result in the serum concentrations as provided herein. when administered to a patient. 0133. In some embodiments, the kit of parts comprises 0.138. In some embodiments, the unit dose of ibogaine, multiple delivery vehicles in a variety of dosing options. For ibogaine derivative, or pharmaceutically acceptable salt and/ example, the kit of parts may comprise pills or tablets in or Solvate thereof is administered in one or more dosings. multiple dosages, such as 240 mg, 120 mg, 90 mg, 60 mg, 30 0.139. In one embodiment, the amount of ibogaine, mg, 20 mg, and/or 10 mg of ibogaine per pill. Each pill is ibogaine derivative, or pharmaceutically acceptable salt and/ labeled Such that the medical professional and/or patient can or Solvate thereof is sufficient to provide an average serum easily distinguish different dosages. Labeling may be based concentration of about 50 ng/mL to about 800 ng/mL or about on printing or embossing on the pill, shape of the pill, color of 60 ng/mL to about 800 ng/mL. In one embodiment, the pill, the location of the pill in a separate, labeled compartment amount of compound is Sufficient to provide an average within the kit, and/or any other distinguishing features of the serum concentration of about 50 ng/mL to about 700 ng/mL pill. In some embodiments, all of the delivery vehicles within or about 60 ng/mL to about 700 ng/mL. In one embodiment, a kit are intended for one patient. In some embodiments, the the amount of compound is Sufficient to provide an average delivery vehicles within a kit are intended for multiple serum concentration of about 50 ng/mL to about 600 ng/mL, patients. or about 60 ng/mL to about 600 ng/mL. In a preferred 0134 One aspect of this invention is directed to a kit of embodiment, the amount of compound is sufficient to provide parts for the modulation of tolerance to an opioid analgesic in an average serum concentration of about 50 ng/mL to about a patient undergoing opioid analgesic therapy, wherein the kit 500 ng/mL, or about 60 ng/mL to about 500 ng/mL. In one comprises a unit dose form of ibogaine, ibogaine derivative, embodiment, the amount of compound is sufficient to provide salt and/or solvate thereof. The unit dose form provides a an average serum concentration of about 50 ng/mL to about patient with an average serum level of ibogaine of from about 400 ng/mL, or about 60 ng/mL to about 400 ng/mL. In one 50 ng/mL to about 800 ng/mL or about 60 ng/mL to about 800 embodiment, the amount of compound is sufficient to provide ng/mL. In one embodiment, the unit dose form provides a an average serum concentration of about 50 ng/mL to about patient with an average serum level of ibogaine of from about 300 ng/mL, or about 60 ng/mL to about 300 ng/mL. In one 50 ng/mL to about 400 ng/mL or about 60 ng/mL to about 400 embodiment, the amount of compound is sufficient to provide ng/mL. an average serum concentration of about 50 ng/mL to about 0135) In some embodiments, the unit dose form comprises 200 ng/mL, or about 60 ng/mL to about 200 ng/mL. In one one or multiple dosages to be administered periodically, Such embodiment, the amount of compound is sufficient to provide as once, twice, three time, four times or five time daily with an average serum concentration of about 50 ng/mL to about ibogaine, ibogaine derivative, orpharmaceutically acceptable 100 ng/mL, or about 60 ng/mL to about 100 ng/mL. The salt and/or Solvate thereof. In some embodiments, the admin ranges include both extremes as well as any Subranges istration is once daily, or once every second day, once every between. third day, three times a week, twice a week, or once a week. 0140. In some embodiments, the formulation is designed The dosage and frequency of the administration depends on for periodic administration, Such as once, twice, three time, criteria including the route of administration, content of com four times or five time daily with ibogaine, ibogaine deriva position, age and body weight of the patient, condition of the tive, or a pharmaceutically acceptable salt and/or Solvate patient, sex of the patient, without limitation, as well as by the thereof. In some embodiments, the administration is once opioid analgesic employed. Determination of the unit dose daily, or once every second day, once every third day, three form providing a dosage and frequency Suitable for a given times a week, twice a week, or once a week. The dosage and patient can readily be made by a qualified clinician. frequency of the administration depends on the route of 0136. These dose ranges may beachieved by transdermal, administration, content of composition, age and body weight oral, or parenteral administration of ibogaine, ibogaine of the patient, condition of the patient, without limitation. derivative, or a pharmaceutically acceptable salt and/or sol Determination of dosage and frequency Suitable for the vate thereof in unit dose form. Such unit dose form may present technology can be readily made a qualified clinician. conveniently be provided in transdermal patch, tablet, caplet, 0.141. In some embodiments, the formulation designed for liquid or capsule form. In certain embodiments, the ibogaine administration in accordance with the methods provide is provided as ibogaine HCl, with dosages reported as the herein can be suitable for a variety of delivery modes includ amount of free base ibogaine. In some embodiments, the ing, without limitation, oral and transdermal delivery. Formu ibogaine HCl is provided in hard gelatin capsules containing lations Suitable for internal, pulmonary, rectal, nasal, vaginal, only ibogaine HCl with no excipients. In some embodiments, lingual, intravenous, intra-arterial, intramuscular, intraperito ibogaine is provided in Saline for intravenous administration. neal, intracutaneous and Subcutaneous routes may also be used. Possible formulations include tablets, capsules, pills, Formulations powders, aerosols, Suppositories, parenterals, and oral liq 0.137 This invention further relates to pharmaceutically uids, including Suspensions, solutions and emulsions. Sus acceptable formulations comprising a unit dose of ibogaine, tained release dosage forms may also be used. All formula ibogaine derivative, or pharmaceutically acceptable salt and/ tions may be prepared using methods that are standard in the or Solvate thereof, wherein the amount of ibogaine, ibogaine art (see e.g., Remington's Pharmaceutical Sciences, 16th ed., derivative, orpharmaceutically acceptable salt and/or Solvate A. Oslo editor, Easton Pa. 1980). thereof is Sufficient to provide an average serum concentra 0142. In a preferred embodiment, the formulation is tion of about 50 ng/mL to about 850 ng/mL when adminis designed for oral administration, which may conveniently be tered to a patient. In a preferred embodiment, the amount of provided in tablet, caplet, Sublingual, liquid or capsule form. US 2015/025811 1 A1 Sep. 17, 2015

In certain embodiments, the ibogaine is provided as ibogaine 4. The method of claim 1, further comprising administer HCl, with dosages reported as the amount of free base ing ibogaine, ibogaine derivative, or pharmaceutically ibogaine. In some embodiments, the ibogaine HCl is pro acceptable salt and/or solvate thereof concurrently with the vided in hard gelatin capsules containing only ibogaine HCl analgesic. with no excipients. 5. The method of claim 4, wherein during concurrent administration, the dose of opioid analgesic is reduced. 6. The method of claim 1, wherein the dose or aggregate EXAMPLES dosage of ibogaine, ibogaine derivative, or pharmaceutically 0143. The following Examples are intended to further acceptable salt and/or solvate thereof is from about 1.3 mg/kg illustrate certain embodiments of the disclosure and are not to about 4 mg/kg per day. 7. The method of claim 1, wherein the aggregate dosage of intended to limit its scope. ibogaine, ibogaine derivative, orpharmaceutically acceptable salt and/or solvate thereof is from about 1.5 mg/kg to about 3 Example 1 mg/kg per day. 8. The method of claim 1, wherein the aggregate dosage of Effect of Ibogaine, Ibogaine Derivative, or a ibogaine, ibogaine derivative, orpharmaceutically acceptable Pharmaceutically Acceptable Salt and/or Solvate salt and/or Solvate thereof is from about 2 mg/kg to about 4 Thereof on QT Interval in Humans mg/kg per day. 9. The method of claim 1, wherein the aggregate dosage of 0144. The effect of ibogaine, ibogaine derivative, or a ibogaine, ibogaine derivative, orpharmaceutically acceptable pharmaceutically acceptable salt and/or Solvate thereof on salt and/or solvate thereof is from about 2 mg/kg to about 3 QT interval is evaluated in Substance-dependent participants mg/kg per day. in a randomized, placebo-controlled, double-blind trial. 10. The method of claim 1, wherein the aggregate dosage Patients are administered 60 mg or 120 mg of the compound of ibogaine, ibogaine derivative, or pharmaceutically accept and QT interval is measured. able salt and/or Solvate thereof is about 2 mg/kg per day. 11. The method of claim 1, wherein the dosage of ibogaine, Example 2 ibogaine derivative, or pharmaceutically acceptable salt and/ or Solvate thereof provides an average serum concentration of Efficacy of Ibogaine to Modulate Opioid Tolerance about 50 ng/mL to about 200 ng/mL. in Humans 12. The method of claim 1, wherein the QT interval is less than about 470 ms. 0145 A female patient, age 59, undergoing opioid anal 13. The method of claim 1, wherein the QT interval is less gesic therapy for chronic back pain, is treated with ibogaine than about 450 ms. hydrochloride at a dose of about 2 mg/kg concurrently with 14. The method of claim 1, further comprising selecting a the opioid. The amount of opioid required to treat her back patient who is prescreened to evaluate tolerance for prolon gation of QT interval. pain after ibogaine treatment is measured. 15. The method of claim 14, wherein the prescreening step What is claimed is: comprises ascertaining that ibogaine treatment will not result 1. A method for modulating tolerance to an opioid analge in a QT interval greater than about 500 ms. sic in a patient undergoing opioid analgesic therapy, the 16. The method of claim 15, wherein the prescreening step method comprising interrupting or administering concur comprises ascertaining that ibogaine treatment will not result rently with said opioid analgesic therapy an amount of in a QT interval greater than about 470 ms. 17. The method of claim 16, wherein the prescreening step ibogaine, ibogaine derivative or pharmaceutically acceptable comprises ascertaining that ibogaine treatment will not result salt and/or Solvate thereof that provides an average serum in a QT interval greater than about 450 ms. concentration of about 50 ng/mL to about 500 ng/mL, said 18. The method of claim 1, wherein the opioid analgesic is concentration being Sufficient to re-sensitize the patient to the selected from the group consisting offentanyl, hydrocodone, opioid as an analgesic while maintaining a QT interval of less hydromorphone, morphine, oxycodone, buprenorphine, than about 500 ms during said treatment. codeine, thebaine, buprenorphine, methadone, meperidine, 2. The method of claim 1, wherein the ibogaine, ibogaine tramadol, tapentadol, levorphanol, Sufentanil, pentazocine, derivative, orpharmaceutically acceptable salt and/or Solvate oxymorphone. thereof is administered as a single dose or multiple doses. 19. The method of claim 18, wherein the opioid analgesic 3. The method of claim 1, further comprising interrupting is morphine. the dosage of the analgesic.