WO2019118205A1 - Procédés de renforcement et/ou d'économie d'opioïdes à partir d'associations co-administrées ou à dose fixe de dronabinol et d'un opioïde - Google Patents

Procédés de renforcement et/ou d'économie d'opioïdes à partir d'associations co-administrées ou à dose fixe de dronabinol et d'un opioïde Download PDF

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WO2019118205A1
WO2019118205A1 PCT/US2018/063284 US2018063284W WO2019118205A1 WO 2019118205 A1 WO2019118205 A1 WO 2019118205A1 US 2018063284 W US2018063284 W US 2018063284W WO 2019118205 A1 WO2019118205 A1 WO 2019118205A1
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micrograms
pharmaceutical combination
amount
present
opioid
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PCT/US2018/063284
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English (en)
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Brent NERGUIZIAN
Kendric SPEAGLE
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Daisy Pharma Opioid Venture, Llc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present disclosure relates to co-administered or fixed-dose pharmaceutical combinations of cannabinoids and opioids for pain management, and more specifically to synergistic combinations comprising dronabinol and one or more of buprenorphine, hydrocodone, codeine, morphine, oxycodone, hydromorphone, oxymorphone, tramadol, and methadone and, in some cases, in further combination with additional active agents such as non-opioid analgesics (e.g., acetaminophen) and/or sedatives (e.g. butalbital).
  • non-opioid analgesics e.g., acetaminophen
  • sedatives e.g. butalbital
  • Opioids have been acknowledged as effective analgesics throughout history. However, the use of opioids for pain management and other indications has been hampered by resultant opioid dependence and addiction, as well as other opioid-induced health problems that develop frequently among patient populations. In fact, over the last two decades, a drastic increase in the use of prescription opioids for the treatment and
  • the present disclosure address this need by providing synergistically effective co administered or fixed-dose combinations of cannabinoids and opioids, which in some embodiments contain further non-opioid analgesics such as acetaminophen and/or sedatives such as butalbital.
  • the synergistically effective co-administered or fixed-dose combinations are useful for treating or preventing pain and other neurotransmitter responsive medical conditions, which utilize lower amounts of opioids than would be required to produce the same, similar or better analgesic effect by opioid therapy alone either by reducing the amount of the opioid or the frequency of dosing.
  • references to co-administered or fixed-dose combinations of cannabinoids and opioids are together referred to herein as“pharmaceutical combinations” regardless of whether the application is co-administered or administered as a fixed-dose combination and whether the opioid component is a single opioid or a combination of opioids.
  • co-administered or fixed-dose combinations of cannabinoids and opioids further include an additional active agents (e.g ., non-opioid analgesics such as acetaminophen or sedatives such as butalbital), it should be understood that these co-administered or fixed-dose combinations may also be referred to as“pharmaceutical combinations” as used herein.
  • an additional active agents e.g ., non-opioid analgesics such as acetaminophen or sedatives such as butalbital
  • the combination therapy of the present disclosure in some aspects achieves an“opioid-sparing” effect—that is, the reduction in opioid dose without compromising pain relief— and may thereafter lead to reduction in opioid-related adverse effects, including opioid use disorder, opioid-induced hyperalgesia, opioid tolerance drift, reduction in the risk of opioid overdose, and reduction in the severity and even incidence of opioid addiction.
  • opioid-related adverse effects including opioid use disorder, opioid-induced hyperalgesia, opioid tolerance drift, reduction in the risk of opioid overdose, and reduction in the severity and even incidence of opioid addiction.
  • the present disclosure provides for a fixed-dose pharmaceutical combination comprising a cannabinoid and an opioid.
  • the cannabinoid and the opioid are each present in an amount such wherein the pharmaceutical combination is synergistically effective.
  • the cannabinoid is dronabinol.
  • the cannabinoid is dronabinol and the opioid is one or more of buprenorphine, hydrocodone, codeine, morphine, oxycodone, hydromorphone, oxymorphone, tramadol, and methadone.
  • the present disclosure provides for a fixed-dose pharmaceutical combination comprising a cannabinoid, an opioid, and a non-opioid analgesic and optionally a sedative.
  • a fixed-dose pharmaceutical combination comprising a cannabinoid, an opioid, and acetaminophen and/or butalbital.
  • a method for pain management comprising administering to a subject in need thereof a fixed-dose pharmaceutical combination comprising a cannabinoid and an opioid.
  • the present disclosure relates to a pharmaceutical combination comprising:
  • the present disclosure relates to a method for pain management comprising administering to a subject in need thereof a pharmaceutical combination as described herein.
  • the present disclosure relates to a method for pain
  • the pain intensity is reduced by at least about 10 percent, at least about 20 percent, at least about 30 percent, at least about 40 percent, at least about 50 percent, at least about 60 percent, or at least about 70 percent or more from a baseline pain intensity; or
  • the amount of opioid present in the pharmaceutical combination is at least about 10 percent, at least about 20 percent, at least about 30 percent, at least about 40 percent, at least about 50 percent, at least about 60 percent, or at least about 70 percent less than the standard opioid dose prescribed for the subject; or
  • the frequency of administration is reduced by at least about 10 percent, at least about 20 percent, at least about 30 percent, at least about 40 percent, at least about 50 percent, at least about 60 percent, or at least about 70 percent from a baseline administration frequency; or
  • FIG. 1 depicts a typical opioid-sparing effect in animal models resulting from use of fixed-dose combinations of an opioid with dronabinol, as compared with opioid therapy alone at the standard dosage.
  • the amount of opioid in the fixed-dose combinations is shown as a percentage of the standard opioid dosage (100%).
  • the following description relates to pharmaceutical combinations comprising cannabinoids and opioids, and optionally further comprising a non-opioid analgesic such as acetaminophen and/or a sedative such as butalbital, and methods of using such
  • a non-opioid analgesic such as acetaminophen and/or a sedative such as butalbital
  • the present disclosure relates to a pharmaceutical combination comprising a cannabinoid and an opioid.
  • the pharmaceutical combination is a fixed-dose combination comprising a cannabinoid and an opioid.
  • the pharmaceutical combination is a co-administered combination comprising a cannabinoid and an opioid.
  • the present disclosure provides for a pharmaceutical combination comprising a cannabinoid, an opioid, and a further non-opioid analgesic, such as acetaminophen.
  • the pharmaceutical combination is a fixed-dose combination comprising a cannabinoid, an opioid and acetaminophen.
  • the pharmaceutical combination is a co-administered combination comprising a cannabinoid and an opioid with acetaminophen.
  • the present disclosure provides for pharmaceutical combinations comprising a cannabinoid, an opioid, a non-opioid analgesic and a sedative.
  • cannabinoids for combination with opioids include dronabinol (deIta-9-tetrahydrocannabinol) and related cannabinoids such as (-)-delta-9- tetrahydrocarmabinol, (H-)-deUa-9 ⁇ tetrabydrocannabinol and delta-8-teirahydroeannabinol, cannabinol, cannabigeroi, eannabicyciol, cannabieisoic acid and their respective pure enantiomers and/or di aster comers, combination of the above cannabinoids, plants extracts containing any or ail of the above cannabinoids (e.g., sativex), any synthetically produced cannabinoids, all naturally occurring cannabinoids, all naturally occurring and synthetically produced stilbenoids and their derived analogs and metabolites, all therapeutically useful and pharmacologically active cannabinoids metabolites
  • dexanabinol dexanabinol
  • all psyehoactive cannabinoids and their analogs e.g. nantradol, nabitan.
  • dronabinol, D-9 tetrahydrocannabinol, D-9 tetrahydrocannabinol and D-9 THC are synonymous.
  • tetrahydrocannabinol D-8 THC, and D-8 tetrahydrocannabinol are synonymous.
  • the amount of cannabinoid present in the pharmaceutical combination is at least about 500 micrograms, at least about 600 micrograms, at least about 700 micrograms, at least about 800 micrograms, or at least about 900 micrograms. In certain embodiments, the amount of cannabinoid present in the pharmaceutical combination is at least about 500 micrograms, at least about 700 micrograms, or at least about 900 micrograms. In other embodiments, the amount of cannabinoid present in the pharmaceutical combination is as least about 600 micrograms, at least about 800 micrograms, or at least about 900 micrograms.
  • the amount of cannabinoid present in the pharmaceutical combination is about 500 micrograms, about 600 micrograms, about 700 micrograms, about 800 micrograms, or about 900 micrograms. In certain embodiments, the amount of cannabinoid present in the pharmaceutical combination is about 500 micrograms or about 900 micrograms.
  • the amount of cannabinoid present in the pharmaceutical combination is at least about 1 mg, at least about 2 mg, at least about 3 mg, at least about 4 mg, at least about 5 mg, at least about 6 mg, at least about 7 mg, at least about 8 mg, at least about 9 mg, at least about 10 mg, at least about 11 mg, at least about 12 mg, at least about 13 mg, at least 14 mg, at least about 15 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, at least about 100 mg, at least about 120 mg, at least about 140 mg, or at least about 160 mg.
  • the cannabinoid present in the pharmaceutical combination is at least about 5 mg, at least about 10 mg, or at least about 20 mg. In some embodiments, the cannabinoid present in the pharmaceutical combination is at least about 5 mg. In some embodiments, the cannabinoid present in the pharmaceutical combination is at least about 10 mg.
  • the amount of cannabinoid present in the pharmaceutical combination is about 1 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 140 mg or about 160 mg.
  • the cannabinoid present in the pharmaceutical combination is between about 1 mg and about 160 mg, between about 1 mg and about 140 mg, between about 1 mg and about 120 mg, between about 1 mg and about 100 mg, between about 1 mg and about 90 mg, between about 1 mg and about 80 mg, between about 1 mg and about 70 mg, between about 1 mg and about 60 mg, between about 1 mg and about 50 mg, between about 1 mg and about 40 mg, between about 1 mg and about 30 mg, between about 1 mg and about 25 mg, between about 1 mg and about 20 mg, between about 1 mg and about 15 mg, between about 1 mg and about 14 mg, between about 1 mg and about 13 mg, between about 1 mg and about 12 mg, between about 1 mg and about 11 mg, between about 1 mg and about 10 mg, between about 1 mg and about 9 mg, between about 1 mg and about 8 mg, between about 1 mg and about 7 mg, between about 1 mg and about 6 mg, between about 1 mg and about 5 mg, between about 1 mg and about 4 mg, between about 1 mg and about 3 mg, between about 1 mg and about 1 mg
  • the cannabinoid is dronabinol.
  • the amount of dronabinol present in the pharmaceutical combination is at least about 500 micrograms, at least about 600 micrograms, at least about 700 micrograms, at least about 800 micrograms, or at least about 900 micrograms.
  • the amount of dronabinol present in the pharmaceutical combination is at least about 500 micrograms, at least about 700 micrograms, or at least about 900 micrograms.
  • the amount of dronabinol present in the pharmaceutical combination is as least about 600 micrograms, at least about 800 micrograms, or at least about 900 micrograms.
  • the amount of dronabinol present in the pharmaceutical combination is about 500 micrograms, about 600 micrograms, about 700 micrograms, about 800 micrograms, or about 900 micrograms. In certain embodiments, the amount of dronabinol present in the pharmaceutical combination is about 500 micrograms or about 900 micrograms.
  • the amount of dronabinol present in the pharmaceutical combination is at least about 1 mg, at least about 2 mg, at least about 3 mg, at least about 4 mg, at least about 5 mg, at least about 6 mg, at least about 7 mg, at least about 8 mg, at least about 9 mg, at least about 10 mg, at least about 11 mg, at least about 12 mg, at least about 13 mg, at least 14 mg, at least about 15 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, at least about 100 mg, at least about 120 mg, at least about 140 mg, or at least about 160 mg.
  • the dronabinol present in the pharmaceutical combination is at least about 5 mg, at least about 10 mg or at least about 20 mg. In some embodiments, the dronabinol present in the pharmaceutical combination is at least about 5 mg. In some embodiments, the dronabinol present in the pharmaceutical combination is at least about 10 mg.
  • the amount of dronabinol present in the pharmaceutical combination is about 1 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 140 mg or about 160 mg.
  • the dronabinol present in the pharmaceutical combination is between about 1 mg and about 160 mg, between about 1 mg and about 140 mg, between about 1 mg and about 120 mg, between about 1 mg and about 100 mg, between about 1 mg and about 90 mg, between about 1 mg and about 80 mg, between about 1 mg and about 70 mg, between about 1 mg and about 60 mg, between about 1 mg and about 50 mg, between about 1 mg and about 40 mg, between about 1 mg and about 30 mg, between about 1 mg and about 25 mg, between about 1 mg and about 20 mg, between about 1 mg and about 15 mg, between about 1 mg and about 14 mg, between about 1 mg and about 13 mg, between about 1 mg and about 12 mg, between about 1 mg and about 11 mg, between about 1 mg and about 10 mg, between about 1 mg and about 9 mg, between about 1 mg and about 8 mg, between about 1 mg and about 7 mg, between about 1 mg and about 6 mg, between about 1 mg and about 5 mg, between about 1 mg and about 4 mg, between about 1 mg and about 3 mg, between about
  • opioids may be combined with the cannabinoids as listed above for the pharmaceutical combination as described herein.
  • opioids for combination with cannabinoids include all therapeutically useful and pharmacologically active opioids and opioid metabolites and their respective pure enantiomers and/or diastereomers.
  • the present disclosure provides for opioids selected from the group consisting of anilopam, pentazocine, dihydroetorphine, phenazocine, sufentanil, codeine, alfentanil, meperidine, morphine, propoxyphene, morphine sulfate ester, tramadol, hydromorphone, buprenorphine, oxymorphone, levorphanol, methadone, L-acetylmethadol, oxycodone, etorphine, hydrocodone, normethadone, remifentanil, noroxycodone, dihydrocodeine, norlevorphanol, ethylmorphine, nalbuphine, hydromorphine, normorphine, dihydroetorphine, and butorphanol.
  • opioids selected from the group consisting of anilopam, pentazocine, dihydroetorphine, phenazocine, sufentanil, codeine, alfent
  • the opioid is buprenorphine, hydrocodone, codeine, morphine, methadone, tramadol, oxymorphone, hydromorphone, or oxycodone.
  • the opioid is buprenorphine, hydrocodone, codeine, or morphine.
  • the opioid is buprenorphine.
  • the opioid is hydrocodone.
  • the opioid is codeine.
  • the opioid is morphine.
  • the opioid is methadone.
  • the opioid is tramadol.
  • the opioid is oxymorphone.
  • the opioid is hydromorphone.
  • the opioid is oxycodone.
  • the amount of opioid present in the pharmaceutical combination is between about 1 microgram and about 1200 mg. In some embodiments, the amount of buprenorphine present in the pharmaceutical combination is between about 1 microgram and about 1200 mg. In other embodiments, the amount of hydrocodone present in the pharmaceutical combination is between about 1 microgram and about 1200 mg. In certain embodiments, the amount of codeine present in the pharmaceutical combination is between about 1 microgram and about 1200 mg. In yet other embodiments, the amount of morphine present in the pharmaceutical combination is between about 1 microgram and about 1200 mg. In still yet other embodiments, the amount of oxycodone present in the pharmaceutical combination is between about 1 microgram and about 1200 mg.
  • the amount of methadone present in the pharmaceutical combination is between about 1 microgram and about 1200 mg. In some embodiments, the amount of hydromorphone present in the pharmaceutical combination is between about 1 microgram and about 1200 mg. In other embodiments, the amount of oxymorphone present in the pharmaceutical combination is between about 1 microgram and about 1200 mg. the amount of tramadol present in the pharmaceutical combination is between about 1 microgram and about 1200 mg.
  • the amount of opioid present in the pharmaceutical combination is at least about 1 microgram, at least about 2 micrograms, at least about 2.5 micrograms, at least about 4 micrograms, at least about 5 micrograms, at least about 10 micrograms, at least about 20 micrograms, or at least about 50 micrograms. In certain embodiments, the amount of opioid present in the pharmaceutical combination is about 1 microgram, about 2 micrograms, about 2.5 micrograms, about 4 micrograms, about 5 micrograms, about 10 micrograms, about 20 micrograms, or about 50 micrograms.
  • the amount of opioid present in the pharmaceutical combination is between about 1 microgram and about 50 micrograms, between about 1 microgram and about 20 micrograms, between about 1 microgram and about 10 micrograms, between about 1 microgram and about 5 micrograms, between about 1 microgram and about 4 micrograms, between about 1 microgram and about 2.5 micrograms, between about 1 microgram and about 2 micrograms, between about 2 micrograms and about 50 micrograms, between about 2 micrograms and about 20 micrograms, between about 2 micrograms and about 10
  • micrograms between about 2 micrograms and about 5 micrograms, between about 2 micrograms and about 4 micrograms, between about 2 micrograms and about 2.5
  • micrograms between about 2.5 micrograms and about 50 micrograms, between about 2.5 micrograms and about 20 micrograms, between about 2.5 micrograms and about 10 micrograms, between about 2.5 micrograms and about 5 micrograms, between about 2.5 micrograms and about 4 micrograms, between about 4 micrograms and about 50 micrograms, between about 4 micrograms and about 20 micrograms, between about 4 micrograms and about 10 micrograms, between about 4 micrograms and about 5 micrograms, between about 5 micrograms and about 50 micrograms, between about 5 micrograms and about 20
  • micrograms between about 5 micrograms and about 10 micrograms, between about 10 micrograms and about 50 micrograms, between about 10 micrograms and about 20 micrograms, or between about 20 micrograms and about 50 micrograms.
  • the amount of opioid present in the pharmaceutical combination is at least about 100 micrograms, at least about 200 micrograms, at least about 300 micrograms, at least about 400 micrograms, at least about 500 micrograms, at least about 700 micrograms, at least about 800 micrograms, or at least about 900 micrograms. In certain embodiments, the amount of opioid present in the pharmaceutical combination is at least about 100 micrograms, at least about 400 micrograms, at least about 700 micrograms, at least about 800 micrograms, or at least about 900 micrograms.
  • the amount of opioid present in the pharmaceutical combination is at least about 100 micrograms, at least about 300 micrograms, at least about 500 micrograms, at least about 700 micrograms, or at least about 900 micrograms. In yet other embodiments, the amount of opioid present in the pharmaceutical combination is at least about 200 micrograms, at least about 400 micrograms, at least about 600 micrograms, or at least about 800 micrograms. In some embodiments, the amount of opioid present in the pharmaceutical combination is at least about 100 micrograms, at least about 500 micrograms, or at least about 900 micrograms.
  • the amount of opioid present in the pharmaceutical combination is about 100 micrograms, about 200 micrograms, about 300 micrograms, about 400 micrograms, about 500 micrograms, about 700 micrograms, about 800 micrograms, or about 900 micrograms. In certain embodiments, the amount of opioid present in the pharmaceutical combination is about 100 micrograms, about 400 micrograms, about 700 micrograms, about 800 micrograms, or about 900 micrograms. In other embodiments, the amount of opioid present in the pharmaceutical combination is about 100 micrograms, about 300 micrograms, about 500 micrograms, about 700 micrograms, or about 900 micrograms.
  • the amount of opioid present in the pharmaceutical combination is about 200 micrograms, about 400 micrograms, about 600 micrograms, or about 800 micrograms. In some embodiments, the amount of opioid present in the pharmaceutical combination is about 100 micrograms, about 500 micrograms, or about 900 micrograms.
  • the amount of opioid present in the pharmaceutical combination is between about 100 micrograms and about 900 micrograms, between about 100 micrograms and about 800 micrograms, between about 100 micrograms and about 700 micrograms, between about 100 micrograms and about 600 micrograms, between about 100 micrograms and about 500 micrograms, between about 100 micrograms and about 400 micrograms, between about 100 micrograms and about 300 micrograms, between about 100 micrograms and about 200 micrograms, between about 200 micrograms and about 900 micrograms, between about 200 micrograms and about 800 micrograms, between about 200 micrograms and about 700 micrograms, between about 200 micrograms and about 600 micrograms, between about 200 micrograms and about 500 micrograms, between about 200 micrograms and about 400 micrograms, between about 200 micrograms and about 300 micrograms, between about 300 micrograms and about 900 micrograms, between about 300 micrograms and about 800 micrograms, between about 300 micrograms and about 700 micrograms, between about 100 micrograms and
  • the amount of opioid present in the pharmaceutical combination is at least about 1 mg, at least about 2 mg, at least about 3 mg, at least about 4 mg, at least about 5 mg, at least about 6 mg, at least about 7 mg, at least about 8 mg, at least about 9 mg, at least about 10 mg, at least about 11 mg, at least about 12 mg, at least about 13 mg, at least about 14 mg, at least about 15 mg, at least about 17 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, at least about 100 mg, at least about 150 mg, at least about 200 mg, at least about 250 mg, at least about 300 mg, at least about 400 mg, at least about 450 mg, at least about 500 mg, at least about 600 mg, at least about 700 mg, at least about 800 mg, at least about 900 mg, at least about 1000 mg, at least about 1100 mg
  • the amount of opioid present in the pharmaceutical combination is about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 17 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, or about 1200 mg.
  • the amount of opioid present in the pharmaceutical combination is between about 1 mg and about 1200 mg, between about 1 mg and about 1100 mg, between about 1 mg and about 1000 mg, between about 1 mg and about 900 mg, between about 1 mg and about 800 mg, between about 1 mg and about 700 mg, between about 1 mg and about 600 mg, between about 1 mg and about 500 mg, between about 1 mg and about 450 mg, between about 1 mg and about 400 mg, between about 1 mg and about 350 mg, between about 1 mg and about 300 mg, between about 1 mg and about 250 mg, between about 1 mg and about 200 mg, between about 1 mg and about 150 mg, between about 1 mg and about 100 mg, between about 1 mg and about 90 mg, between about 1 mg and about 80 mg, between about 1 mg and about 70 mg, between about 1 mg and about 60 mg, between about 1 mg and about 50 mg, between about 1 mg and about 40 mg, between about 1 mg and about 30 mg, between about 1 mg and about 25 mg, between about 1 mg and about 20 mg, between about 1 mg and about 15 mg, between about
  • the amount of opioid present in the pharmaceutical combination is at least about 1 mg, at least about 2 mg, at least about 2.5 mg, at least about 4 mg, at least about 5 mg, at least about 7.5 mg, at least about 8 mg, at least about 10 mg, at least about 15 mg, or at least about 30 mg.
  • the amount of opioid present in the pharmaceutical combination is between about 1 mg and about 5 mg, between about 1 and about 8 mg, between about 5 mg and about 15 mg, or between about 7.5 mg and about 30 mg.
  • the opioid is buprenorphine.
  • the amount of buprenorphine present in the pharmaceutical combination is at least about 1 microgram, at least about 2 micrograms, at least about 2.5 micrograms, at least about 4 micrograms, at least about 5 micrograms, at least about 10 micrograms, at least about 20 micrograms, or at least about 50 micrograms. In certain embodiments, the amount of buprenorphine present in the pharmaceutical combination is about 1 microgram, about 2 micrograms, about 2.5 micrograms, about 4 micrograms, about 5 micrograms, about 10 micrograms, about 20 micrograms, or about 50 micrograms.
  • the amount of buprenorphine present in the pharmaceutical combination is between about 1 microgram and about 50 micrograms, between about 1 microgram and about 20 micrograms, between about 1 microgram and about 10 micrograms, between about 1 microgram and about 5 micrograms, between about 1 microgram and about 4 micrograms, between about 1 microgram and about 2.5 micrograms, between about 1 microgram and about 2 micrograms, between about 2 micrograms and about 50 micrograms, between about 2 micrograms and about 20 micrograms, between about 2 micrograms and about 10 micrograms, between about 2 micrograms and about 5 micrograms, between about 2 micrograms and about 4
  • micrograms between about 2 micrograms and about 2.5 micrograms, between about 2.5 micrograms and about 50 micrograms, between about 2.5 micrograms and about 20 micrograms, between about 2.5 micrograms and about 10 micrograms, between about 2.5 micrograms and about 5 micrograms, between about 2.5 micrograms and about 4
  • micrograms between about 4 micrograms and about 50 micrograms, between about 4 micrograms and about 20 micrograms, between about 4 micrograms and about 10
  • micrograms between about 4 micrograms and about 5 micrograms, between about 5 micrograms and about 50 micrograms, between about 5 micrograms and about 20
  • micrograms between about 5 micrograms and about 10 micrograms, between about 10 micrograms and about 50 micrograms, between about 10 micrograms and about 20 micrograms, or between about 20 micrograms and about 50 micrograms.
  • the amount of buprenorphine present in the pharmaceutical combination is at least about 100 micrograms, at least about 200 micrograms, at least about 300 micrograms, at least about 400 micrograms, at least about 500 micrograms, at least about 700 micrograms, at least about 800 micrograms, or at least about 900 micrograms. In certain embodiments, the amount of buprenorphine present in the pharmaceutical combination is at least about 100 micrograms, at least about 400 micrograms, at least about 700 micrograms, at least about 800 micrograms, or at least about 900 micrograms.
  • the amount of buprenorphine present in the pharmaceutical combination is at least about 100 micrograms, at least about 300 micrograms, at least about 500 micrograms, at least about 700 micrograms, or at least about 900 micrograms. In yet other embodiments, the amount of buprenorphine present in the pharmaceutical combination is at least about 200 micrograms, at least about 400 micrograms, at least about 600 micrograms, or at least about 800 micrograms. In some embodiments, the amount of buprenorphine present in the pharmaceutical combination is at least about 100 micrograms, at least about 500 micrograms, or at least about 900 micrograms.
  • the amount of buprenorphine present in the pharmaceutical combination is about 100 micrograms, about 200 micrograms, about 300 micrograms, about 400 micrograms, about 500 micrograms, about 700 micrograms, about 800 micrograms, or about 900 micrograms. In certain embodiments, the amount of buprenorphine present in the pharmaceutical combination is about 100 micrograms, about 400 micrograms, about 700 micrograms, about 800 micrograms, or about 900 micrograms. In other embodiments, the amount of buprenorphine present in the pharmaceutical combination is about 100
  • the amount of buprenorphine present in the pharmaceutical combination is about 200 micrograms, about 400 micrograms, about 600 micrograms, or about 800 micrograms. In some embodiments, the amount of buprenorphine present in the pharmaceutical combination is about 100 micrograms, about 500 micrograms, or about 900 micrograms.
  • the amount of buprenorphine present in the pharmaceutical combination is between about 100 micrograms and about 900 micrograms, between about 100 micrograms and about 800 micrograms, between about 100 micrograms and about 700 micrograms, between about 100 micrograms and about 600 micrograms, between about 100 micrograms and about 500 micrograms, between about 100 micrograms and about 400 micrograms, between about 100 micrograms and about 300 micrograms, between about 100 micrograms and about 200 micrograms, between about 200 micrograms and about 900 micrograms, between about 200 micrograms and about 800 micrograms, between about 200 micrograms and about 700 micrograms, between about 200 micrograms and about 600 micrograms, between about 200 micrograms and about 500 micrograms, between about 200 micrograms and about 400 micrograms, between about 200 micrograms and about 300 micrograms, between about 300 micrograms and about 900 micrograms, between about 300 micrograms and about 800 micrograms, between about 300 micrograms and about 700 micrograms, between about
  • micrograms and about 900 micrograms.
  • the amount of buprenorphine present in the pharmaceutical combination is at least about 100 micrograms, at least about 200 micrograms, at least about 250 micrograms, at least about 400 micrograms, at least about 500 micrograms, at least about 700 micrograms, or at least about 800 micrograms. In certain embodiments, the amount of buprenorphine present in the pharmaceutical combination is between about 100 micrograms and about 400 micrograms, between about 100 micrograms and about 800 micrograms, or between about 400 micrograms and about 800 micrograms. In other embodiments, the amount of buprenorphine present in the pharmaceutical combination is about 100
  • the amount of buprenorphine present in the pharmaceutical combination is 100 micrograms. In other embodiments, the amount of buprenorphine present in the pharmaceutical combination is 400 micrograms. In yet other embodiments, the amount of buprenorphine present in the pharmaceutical combination is 800 micrograms.
  • the amount of buprenorphine present in the pharmaceutical combination is at least about 1 mg, at least about 2 mg, at least about 3 mg, at least about 4 mg, at least about 5 mg, at least about 6 mg, at least about 7 mg, at least about 8 mg, at least about 9 mg, at least about 10 mg, at least about 11 mg, at least about 12 mg, at least about 13 mg, at least about 14 mg, at least about 15 mg, at least about 17 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, at least about
  • the amount of buprenorphine present in the pharmaceutical combination is about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 6.
  • the amount of buprenorphine present in the pharmaceutical combination is between about 1 mg and about 1200 mg, between about 1 mg and about 1100 mg, between about 1 mg and about 1000 mg, between about 1 mg and about 900 mg, between about 1 mg and about 800 mg, between about 1 mg and about 700 mg, between about 1 mg and about 600 mg, between about 1 mg and about 500 mg, between about 1 mg and about 450 mg, between about 1 mg and about 400 mg, between about 1 mg and about 350 mg, between about 1 mg and about 300 mg, between about 1 mg and about 250 mg, between about 1 mg and about 200 mg, between about 1 mg and about 150 mg, between about 1 mg and about 100 mg, between about 1 mg and about 90 mg, between about 1 mg and about 80 mg, between about 1 mg and about 70 mg, between about 1 mg and about 60 mg, between about 1 mg and about 50 mg, between about 1 mg and about 40 mg, between about 1 mg and about 30 mg, between about 1 mg and about 25 mg, between about 1 mg and about 20 mg, between about 1 mg and about 15 mg,
  • the amount of buprenorphine present in the pharmaceutical combination is at least about 1 mg, at least about 2 mg, at least about 2.5 mg, at least about 4 mg, at least about 5 mg, at least about 7.5 mg, at least about 8 mg, at least about 10 mg, at least about 15 mg, or at least about 30 mg. In certain embodiments, the amount of buprenorphine present in the pharmaceutical
  • combination is between about 1 mg and about 5 mg, between about 1 and about 8 mg, between about 5 mg and about 15 mg, or between about 7.5 mg and about 30 mg.
  • the pharmaceutical combination is at least about 1 mg, at least about 2 mg, at least about 2.5 mg, at least about 4 mg, at least about 5 mg, at least about 7 mg, at least about 8 mg, at least about 10 mg, at least about 12 mg, at least about 15 mg, at least about 20 mg, or at least about 24 mg.
  • the amount of buprenorphine present in the pharmaceutical combination is between about 1 mg and about 4 mg, between about 1 mg and about 6.4 mg, between about 1 mg and about 8 mg, between about 4 mg and about 8 mg, between about 1 mg and about 10 mg, between about 10 mg and about 15 mg, or between about 15 mg and about 24 mg. In other embodiments, the amount of buprenorphine present in the
  • the pharmaceutical combination is about 1 mg, about 4 mg, about 6.4 mg, about 8 mg, about 10 mg, about 12 mg, about 15 mg, about 20 mg, or about 24 mg.
  • the amount of buprenorphine present in the pharmaceutical combination is about 1 mg, about 2 mg, or about 6.4 mg.
  • the amount of buprenorphine present in the pharmaceutical combination is about 8 mg, about 10 mg, about 12 mg, about 15 mg, about 20 mg, or about 24 mg.
  • the amount of buprenorphine present in the pharmaceutical combination is about 1 mg. In other embodiments, the amount of
  • buprenorphine present in the pharmaceutical combination is about 4 mg. In other words,
  • the amount of buprenorphine present in the pharmaceutical combination is about 6.4 mg. In yet other embodiments, the amount of buprenorphine present in the pharmaceutical combination is about 8 mg. In other embodiments, the amount of
  • buprenorphine present in the pharmaceutical combination is about 10 mg. In some embodiments, the amount of buprenorphine present in the pharmaceutical combination is about 12 mg. In other embodiments, the amount of buprenorphine present in the
  • the pharmaceutical combination is about 15 mg. In yet other embodiments, the amount of buprenorphine present in the pharmaceutical combination is 20 mg. In still yet other embodiments, the amount of buprenorphine present in the pharmaceutical combination is 24 mg.
  • the opioid is hydrocodone.
  • the amount of hydrocodone present in the pharmaceutical combination is at least about 1 microgram, at least about 2 micrograms, at least about 2.5 micrograms, at least about 4 micrograms, at least about 5 micrograms, at least about 10 micrograms, at least about 20 micrograms, or at least about 50 micrograms. In certain embodiments, the amount of hydrocodone present in the pharmaceutical combination is about 1 microgram, about 2 micrograms, about 2.5 micrograms, about 4 micrograms, about 5 micrograms, about 10 micrograms, about 20 micrograms, or about 50 micrograms.
  • the amount of hydrocodone present in the pharmaceutical combination is between about 1 microgram and about 50 micrograms, between about 1 microgram and about 20 micrograms, between about 1 microgram and about 10 micrograms, between about 1 microgram and about 5 micrograms, between about 1 microgram and about 4 micrograms, between about 1 microgram and about 2.5 micrograms, between about 1 microgram and about 2 micrograms, between about 2 micrograms and about 50 micrograms, between about 2 micrograms and about 20 micrograms, between about 2 micrograms and about 10 micrograms, between about 2 micrograms and about 5 micrograms, between about 2 micrograms and about 4
  • micrograms between about 2 micrograms and about 2.5 micrograms, between about 2.5 micrograms and about 50 micrograms, between about 2.5 micrograms and about 20 micrograms, between about 2.5 micrograms and about 10 micrograms, between about 2.5 micrograms and about 5 micrograms, between about 2.5 micrograms and about 4
  • micrograms between about 4 micrograms and about 50 micrograms, between about 4 micrograms and about 20 micrograms, between about 4 micrograms and about 10
  • micrograms between about 4 micrograms and about 5 micrograms, between about 5 micrograms and about 50 micrograms, between about 5 micrograms and about 20
  • micrograms between about 5 micrograms and about 10 micrograms, between about 10 micrograms and about 50 micrograms, between about 10 micrograms and about 20 micrograms, or between about 20 micrograms and about 50 micrograms.
  • the amount of hydrocodone present in the pharmaceutical combination is at least about 100 micrograms, at least about 200 micrograms, at least about 300 micrograms, at least about 400 micrograms, at least about 500 micrograms, at least about 700 micrograms, at least about 800 micrograms, or at least about 900 micrograms. In certain embodiments, the amount of hydrocodone present in the pharmaceutical combination is at least about 100 micrograms, at least about 400 micrograms, at least about 700 micrograms, at least about 800 micrograms, or at least about 900 micrograms.
  • the amount of hydrocodone present in the pharmaceutical combination is at least about 100 micrograms, at least about 300 micrograms, at least about 500 micrograms, at least about 700 micrograms, or at least about 900 micrograms. In yet other embodiments, the amount of hydrocodone present in the pharmaceutical combination is at least about 200 micrograms, at least about 400 micrograms, at least about 600 micrograms, or at least about 800 micrograms. In some embodiments, the amount of hydrocodone present in the pharmaceutical combination is at least about 100 micrograms, at least about 500 micrograms, or at least about 900 micrograms.
  • the amount of hydrocodone present in the pharmaceutical combination is about 100 micrograms, about 200 micrograms, about 300 micrograms, about 400 micrograms, about 500 micrograms, about 700 micrograms, about 800 micrograms, or about 900 micrograms. In certain embodiments, the amount of hydrocodone present in the pharmaceutical combination is about 100 micrograms, about 400 micrograms, about 700 micrograms, about 800 micrograms, or about 900 micrograms. In other embodiments, the amount of hydrocodone present in the pharmaceutical combination is about 100 micrograms, about 300 micrograms, about 500 micrograms, about 700 micrograms, or about 900 micrograms.
  • the amount of hydrocodone present in the pharmaceutical combination is about 200 micrograms, about 400 micrograms, about 600 micrograms, or about 800 micrograms. In some embodiments, the amount of hydrocodone present in the pharmaceutical combination is about 100 micrograms, about 500 micrograms, or about 900 micrograms.
  • the amount of hydrocodone present in the pharmaceutical combination is between about 100 micrograms and about 900 micrograms, between about 100 micrograms and about 800 micrograms, between about 100 micrograms and about 700 micrograms, between about 100 micrograms and about 600 micrograms, between about 100 micrograms and about 500 micrograms, between about 100 micrograms and about 400 micrograms, between about 100 micrograms and about 300 micrograms, between about 100 micrograms and about 200 micrograms, between about 200 micrograms and about 900 micrograms, between about 200 micrograms and about 800 micrograms, between about 200 micrograms and about 700 micrograms, between about 200 micrograms and about 600 micrograms, between about 200 micrograms and about 500 micrograms, between about 200 micrograms and about 400 micrograms, between about 200 micrograms and about 300 micrograms, between about 300 micrograms and about 900 micrograms, between about 300 micrograms and about 800 micrograms, between about 300 micrograms and about 700 micrograms, between about 100 micro
  • the amount of hydrocodone present in the pharmaceutical combination is at least about 1 mg, at least about 2 mg, at least about 3 mg, at least about 4 mg, at least about 5 mg, at least about 6 mg, at least about 7 mg, at least about 8 mg, at least about 9 mg, at least about 10 mg, at least about 11 mg, at least about 12 mg, at least about 13 mg, at least about 14 mg, at least about 15 mg, at least about 17 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, at least about 100 mg, at least about 150 mg, at least about 200 mg, at least about 250 mg, at least about 300 mg, at least about 400 mg, at least about 450 mg, at least about 500 mg, at least about 600 mg, at least about 700 mg, at least about 800 mg, at least about 900 mg, at least about 1000 mg, at least about
  • the amount of hydrocodone present in the pharmaceutical combination is about 1 mg, about 1.25 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 7.5 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 17 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 96 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, or about 1200 mg.
  • the amount of hydrocodone present in the pharmaceutical combination is between about 1 mg and about 1200 mg, between about 1 mg and about 1100 mg, between about 1 mg and about 1000 mg, between about 1 mg and about 900 mg, between about 1 mg and about 800 mg, between about 1 mg and about 700 mg, between about 1 mg and about 600 mg, between about 1 mg and about 500 mg, between about 1 mg and about 450 mg, between about 1 mg and about 400 mg, between about 1 mg and about 350 mg, between about 1 mg and about 300 mg, between about 1 mg and about 250 mg, between about 1 mg and about 200 mg, between about 1 mg and about 150 mg, between about 1 mg and about 100 mg, between about 1 mg and 96 mg, between about 1 .25 mg and about 96 mg, between about 1 mg and about 90 mg, between about 1 mg and about 80 mg, between about 1 mg and about 70 mg, between about 1 mg and about 60 mg, between about 1 mg and about 50 mg, between about 1 mg and about 40 mg, between about 1 mg and about 30 mg, between about 1 mg and about 1 mg
  • the amount of hydrocodone present in the pharmaceutical combination is at least about 1 mg, at least about 2 mg, at least about 2.5 mg, at least about 4 mg, at least about 5 mg, at least about 7.5 mg, at least about 8 mg, at least about 10 mg, at least about 15 mg, or at least about 30 mg. In certain embodiments, the amount of hydrocodone present in the pharmaceutical combination is between about 1 mg and about 5 mg, between about 1 and about 8 mg, between about 5 mg and about 15 mg, or between about 7.5 mg and about 30 mg. In other embodiments, the amount of hydrocodone present in the pharmaceutical combination is between about 1 mg and about 100 mg, between about 1 mg and about 96 mg or between about 1.25 mg and about 96 mg.
  • the amount of hydrocodone present in the pharmaceutical combination is at least about 1 mg, at least about 2 mg, at least about 2.5 mg, at least about 4 mg, at least about 5 mg, at least about 7.5 mg, at least about 10 mg, at least about 15 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, or at least about 40 mg. In certain embodiments, the amount of hydrocodone present in the pharmaceutical combination is between about 1 mg and about 5 mg. In some embodiments, the amount of hydrocodone present in the pharmaceutical combination is between about 10 mg and about 15 mg. In other embodiments, the amount of hydrocodone present in the pharmaceutical combination is about 1 mg, about 2.5 mg, or about 5 mg.
  • the amount of hydrocodone present in the pharmaceutical combination is about 10 mg, about 15 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg. In some embodiments, the amount of hydrocodone present in the pharmaceutical combination is about 1 mg. In other embodiments, the amount of hydrocodone present in the pharmaceutical combination is about 2.5 mg. In yet other embodiments, the amount of hydrocodone present in the pharmaceutical combination is about 5 mg. In still yet other embodiments, the amount of hydrocodone present in the
  • pharmaceutical combination is about 1.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 60 mg, about 80 mg, about 96 mg, or about 100 mg.
  • the opioid is codeine.
  • the amount of codeine present in the pharmaceutical combination is at least about 1 microgram, at least about 2 micrograms, at least about 2.5 micrograms, at least about 4 micrograms, at least about 5 micrograms, at least about 10 micrograms, at least about 20 micrograms, or at least about 50 micrograms. In certain embodiments, the amount of codeine present in the pharmaceutical combination is about 1 microgram, about 2 micrograms, about 2.5 micrograms, about 4 micrograms, about 5 micrograms, about 10 micrograms, about 20 micrograms, or about 50 micrograms.
  • the amount of codeine present in the pharmaceutical combination is between about 1 microgram and about 50 micrograms, between about 1 microgram and about 20 micrograms, between about 1 microgram and about 10 micrograms, between about 1 microgram and about 5 micrograms, between about 1 microgram and about 4 micrograms, between about 1 microgram and about 2.5 micrograms, between about 1 microgram and about 2 micrograms, between about 2 micrograms and about 50 micrograms, between about 2 micrograms and about 20 micrograms, between about 2 micrograms and about 10 micrograms, between about 2 micrograms and about 5 micrograms, between about 2 micrograms and about 4 micrograms, between about 2 micrograms and about 2.5 micrograms, between about 2.5 micrograms and about 50 micrograms, between about 2.5 micrograms and about 20 micrograms, between about 2.5 micrograms and about 10 micrograms, between about 2.5 micrograms and about 5 micrograms, between about 2.5 micrograms and about 4 micrograms, between about 4 micrograms and about 50 micrograms, between about 1
  • micrograms between about 5 micrograms and about 10 micrograms, between about 10 micrograms and about 50 micrograms, between about 10 micrograms and about 20 micrograms, or between about 20 micrograms and about 50 micrograms.
  • the amount of codeine present in the pharmaceutical combination is at least about 100 micrograms, at least about 200 micrograms, at least about 300 micrograms, at least about 400 micrograms, at least about 500 micrograms, at least about 700 micrograms, at least about 800 micrograms, or at least about 900 micrograms. In certain embodiments, the amount of codeine present in the pharmaceutical combination is at least about 100 micrograms, at least about 400 micrograms, at least about 700 micrograms, at least about 800 micrograms, or at least about 900 micrograms.
  • the amount of codeine present in the pharmaceutical combination is at least about 100 micrograms, at least about 300 micrograms, at least about 500 micrograms, at least about 700 micrograms, or at least about 900 micrograms. In yet other embodiments, the amount of codeine present in the pharmaceutical combination is at least about 200 micrograms, at least about 400 micrograms, at least about 600 micrograms, or at least about 800 micrograms. In some embodiments, the amount of codeine present in the pharmaceutical combination is at least about 100 micrograms, at least about 500 micrograms, or at least about 900 micrograms.
  • the amount of codeine present in the pharmaceutical combination is about 100 micrograms, about 200 micrograms, about 300 micrograms, about 400 micrograms, about 500 micrograms, about 700 micrograms, about 800 micrograms, or about 900 micrograms. In certain embodiments, the amount of codeine present in the pharmaceutical combination is about 100 micrograms, about 400 micrograms, about 700 micrograms, about 800 micrograms, or about 900 micrograms. In other embodiments, the amount of codeine present in the pharmaceutical combination is about 100 micrograms, about 300 micrograms, about 500 micrograms, about 700 micrograms, or about 900 micrograms.
  • the amount of codeine present in the pharmaceutical combination is about 200 micrograms, about 400 micrograms, about 600 micrograms, or about 800 micrograms. In some embodiments, the amount of codeine present in the pharmaceutical combination is about 100 micrograms, about 500 micrograms, or about 900 micrograms.
  • the amount of codeine present in the pharmaceutical combination is between about 100 micrograms and about 900 micrograms, between about 100 micrograms and about 800 micrograms, between about 100 micrograms and about 700 micrograms, between about 100 micrograms and about 600 micrograms, between about 100 micrograms and about 500 micrograms, between about 100 micrograms and about 400 micrograms, between about 100 micrograms and about 300 micrograms, between about 100 micrograms and about 200 micrograms, between about 200 micrograms and about 900 micrograms, between about 200 micrograms and about 800 micrograms, between about 200 micrograms and about 700 micrograms, between about 200 micrograms and about 600 micrograms, between about 200 micrograms and about 500 micrograms, between about 200 micrograms and about 400 micrograms, between about 200 micrograms and about 300 micrograms, between about 300 micrograms and about 900 micrograms, between about 300 micrograms and about 800 micrograms, between about 300 micrograms and about 700 micrograms, between about 100 micrograms
  • the amount of codeine present in the pharmaceutical combination is at least about 1 mg, at least about 2 mg, at least about 3 mg, at least about 4 mg, at least about 5 mg, at least about 6 mg, at least about 7 mg, at least about 8 mg, at least about 9 mg, at least about 10 mg, at least about 11 mg, at least about 12 mg, at least about 13 mg, at least about 14 mg, at least about 15 mg, at least about 17 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, at least about
  • the amount of codeine present in the pharmaceutical combination is about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 7.5 mg about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 17 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 48 mg about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, or about 1200 mg.
  • the amount of codeine present in the pharmaceutical combination is about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 7.5 mg about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14
  • the amount of codeine present in the pharmaceutical combination is between about 1 mg and about 1200 mg, between about 1 mg and about 1100 mg, between about 1 mg and about 1000 mg, between about 1 mg and about 900 mg, between about 1 mg and about 800 mg, between about 1 mg and about 700 mg, between about 1 mg and about 600 mg, between about 1 mg and about 500 mg, between about 1 mg and about 450 mg, between about 1 mg and about 400 mg, between about 1 mg and about 350 mg, between about 1 mg and about 300 mg, between about 1 mg and about 250 mg, between about 1 mg and about 200 mg, between about 1 mg and about 150 mg, between about 1 mg and about 100 mg, between about 1 mg and about 90 mg, between about 1 mg and about 80 mg, between about 1 mg and about 70 mg, between about 1 mg and about 60 mg, between about 1 mg and about 50 mg, between about 1 mg and about 40 mg, between about 1 mg and about 30 mg, between about 1 mg and about 25 mg, between about 1 mg and about 20 mg, between about 1 mg and about 15 mg, between about 1 mg and
  • the amount of codeine present in the pharmaceutical combination is at least about 1 mg, at least about 2 mg, at least about 2.5 mg, at least about 4 mg, at least about 5 mg, at least about 7.5 mg, at least about 8 mg, at least about 10 mg, at least about 15 mg, or at least about 30 mg. In certain embodiments, the amount of codeine present in the pharmaceutical combination is between about 1 mg and about 5 mg, between about 1 and about 8 mg, between about 5 mg and about 15 mg, between about 7.5 mg and about 30 mg, or between about 7.5 mg and about 48 mg.
  • the amount of codeine present in the pharmaceutical combination is at least about 5 mg, at least about 7.5 mg, at least about 8 mg, at least about 10 mg, at least about 15 mg, at least about 30 mg, at least about 50 mg, at least about 75 mg, or at least about 100 mg. In certain embodiments, the amount of codeine present in the pharmaceutical combination is between about 5 mg and 30 mg, between about 5 mg and 15 mg, between about 7.5 mg and about 48 mg, between about 7.5 mg and about 30 mg, between about 7.5 mg and about 15 mg, between about 15 mg and about 30 mg, between about 30 mg and about 50 mg, between about 50 mg and about 75 mg, or between about 75 mg and about 100 mg.
  • the amount of codeine present in the pharmaceutical combination is about 7.5 mg, about 15 mg, about 30 mg, or about 48 mg. In some embodiments, the amount of codeine present in the pharmaceutical combination is about 7.5 mg. In other embodiments, the amount of codeine present in the pharmaceutical combination is about 15 mg. In yet other embodiments, the amount of codeine present in the pharmaceutical combination is about 30 mg. In other embodiments, the amount of codeine present in the pharmaceutical combination is about 48 mg. In still yet other embodiments, the amount of codeine present in the pharmaceutical combination is about 100 mg.
  • the opioid is morphine.
  • the amount of morphine present in the pharmaceutical combination is at least about 1 microgram, at least about 2 micrograms, at least about 2.5 micrograms, at least about 4 micrograms, at least about 5 micrograms, at least about 10 micrograms, at least about 20 micrograms, or at least about 50 micrograms. In certain embodiments, the amount of morphine present in the pharmaceutical combination is about 1 microgram, about 2 micrograms, about 2.5 micrograms, about 4 micrograms, about 5 micrograms, about 10 micrograms, about 20 micrograms, or about 50 micrograms.
  • the amount of morphine present in the pharmaceutical combination is between about 1 microgram and about 50 micrograms, between about 1 microgram and about 20 micrograms, between about 1 microgram and about 10 micrograms, between about 1 microgram and about 5 micrograms, between about 1 microgram and about 4 micrograms, between about 1 microgram and about 2.5 micrograms, between about 1 microgram and about 2 micrograms, between about 2 micrograms and about 50 micrograms, between about 2 micrograms and about 20 micrograms, between about 2 micrograms and about 10 micrograms, between about 2 micrograms and about 5 micrograms, between about 2 micrograms and about 4
  • micrograms between about 2 micrograms and about 2.5 micrograms, between about 2.5 micrograms and about 50 micrograms, between about 2.5 micrograms and about 20 micrograms, between about 2.5 micrograms and about 10 micrograms, between about 2.5 micrograms and about 5 micrograms, between about 2.5 micrograms and about 4
  • micrograms between about 4 micrograms and about 50 micrograms, between about 4 micrograms and about 20 micrograms, between about 4 micrograms and about 10
  • micrograms between about 4 micrograms and about 5 micrograms, between about 5 micrograms and about 50 micrograms, between about 5 micrograms and about 20
  • micrograms between about 5 micrograms and about 10 micrograms, between about 10 micrograms and about 50 micrograms, between about 10 micrograms and about 20 micrograms, or between about 20 micrograms and about 50 micrograms.
  • the amount of morphine present in the pharmaceutical combination is at least about 100 micrograms, at least about 200 micrograms, at least about 300 micrograms, at least about 400 micrograms, at least about 500 micrograms, at least about 700 micrograms, at least about 800 micrograms, or at least about 900 micrograms. In certain embodiments, the amount of morphine present in the pharmaceutical combination is at least about 100 micrograms, at least about 400 micrograms, at least about 700 micrograms, at least about 800 micrograms, or at least about 900 micrograms.
  • the amount of morphine present in the pharmaceutical combination is at least about 100 micrograms, at least about 300 micrograms, at least about 500 micrograms, at least about 700 micrograms, or at least about 900 micrograms. In yet other embodiments, the amount of morphine present in the pharmaceutical combination is at least about 200 micrograms, at least about 400 micrograms, at least about 600 micrograms, or at least about 800 micrograms. In some embodiments, the amount of morphine present in the pharmaceutical combination is at least about 100 micrograms, at least about 500 micrograms, or at least about 900 micrograms.
  • the amount of morphine present in the pharmaceutical combination is about 100 micrograms, about 200 micrograms, about 300 micrograms, about 400 micrograms, about 500 micrograms, about 700 micrograms, about 800 micrograms, or about 900 micrograms. In certain embodiments, the amount of morphine present in the pharmaceutical combination is about 100 micrograms, about 400 micrograms, about 700 micrograms, about 800 micrograms, or about 900 micrograms. In other embodiments, the amount of morphine present in the pharmaceutical combination is about 100 micrograms, about 300 micrograms, about 500 micrograms, about 700 micrograms, or about 900 micrograms. In yet other embodiments, the amount of morphine present in the
  • the pharmaceutical combination is about 200 micrograms, about 400 micrograms, about 600 micrograms, or about 800 micrograms. In some embodiments, the amount of morphine present in the pharmaceutical combination is about 100 micrograms, about 500 micrograms, or about 900 micrograms.
  • the amount of morphine present in the pharmaceutical combination is between about 100 micrograms and about 900 micrograms, between about 100 micrograms and about 800 micrograms, between about 100 micrograms and about 700 micrograms, between about 100 micrograms and about 600 micrograms, between about 100 micrograms and about 500 micrograms, between about 100 micrograms and about 400 micrograms, between about 100 micrograms and about 300 micrograms, between about 100 micrograms and about 200 micrograms, between about 200 micrograms and about 900 micrograms, between about 200 micrograms and about 800 micrograms, between about 200 micrograms and about 700 micrograms, between about 200 micrograms and about 600 micrograms, between about 200 micrograms and about 500 micrograms, between about 200 micrograms and about 400 micrograms, between about 200 micrograms and about 300 micrograms, between about 300 micrograms and about 900 micrograms, between about 300 micrograms and about 800 micrograms, between about 300 micrograms and about 700 micrograms, between about 100 microgram
  • micrograms and about 900 micrograms.
  • the amount of morphine present in the pharmaceutical combination is at least about 1 mg, at least about 2 mg, at least about 3 mg, at least about 4 mg, at least about 5 mg, at least about 6 mg, at least about 7 mg, at least about 8 mg, at least about 9 mg, at least about 10 mg, at least about 11 mg, at least about 12 mg, at least about 13 mg, at least about 14 mg, at least about 15 mg, at least about 17 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, at least about
  • the amount of morphine present in the pharmaceutical combination is about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 17 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 130 mg, about 150 mg, about 160 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, or about 1200 mg.
  • the amount of morphine present in the pharmaceutical combination is between about 1 mg and about 1200 mg, between about 1 mg and about 1100 mg, between about 1 mg and about 1000 mg, between about 1 mg and about 900 mg, between about 1 mg and about 800 mg, between about 1 mg and about 700 mg, between about 1 mg and about 600 mg, between about 1 mg and about 500 mg, between about 1 mg and about 450 mg, between about 1 mg and about 400 mg, between about 1 mg and about 350 mg, between about 1 mg and about 300 mg, between about 1 mg and about 250 mg, between about 1 mg and about 200 mg, between about 1 mg and about 150 mg, between about 1 mg and about 100 mg, between about 1 mg and about 90 mg, between about 1 mg and about 80 mg, between about 1 mg and about 70 mg, between about 1 mg and about 60 mg, between about 1 mg and about 50 mg, between about 1 mg and about 40 mg, between about 1 mg and about 30 mg, between about 1 mg and about 25 mg, between about 1 mg and about 20 mg, between about 1 mg and about 15 mg,
  • the amount of morphine present in the pharmaceutical combination is at least about 1 mg, at least about 2 mg, at least about 2.5 mg, at least about 4 mg, at least about 5 mg, at least about 7.5 mg, at least about 8 mg, at least about 10 mg, at least about 15 mg, or at least about 30 mg.
  • the amount of morphine present in the pharmaceutical combination is between about 1 mg and about 5 mg, between about 1 and about 8 mg, between about 5 mg and about 15 mg, or between about 7.5 mg and about 30 mg.
  • the amount of morphine present in the pharmaceutical combination is at least about 1 mg, at least about 2.5 mg, at least about 5 mg, at least about 7.5 mg, at least about 10 mg, or at least about 15 mg. In certain embodiments, the amount of morphine present in the pharmaceutical combination is between about 1 mg and about 5 mg, between about 5 mg and 10 mg, between about 5 mg and about 15 mg, or between about 10 mg and 15 mg. In other embodiments, the amount of morphine present in the pharmaceutical combination is at least about 1 mg, at least about 2.5 mg, at least about 5 mg, at least about 10 mg, or at least about 15 mg. In some embodiments, the amount of morphine present in the pharmaceutical combination is at least about 5 mg. In other embodiments, the amount of morphine present in the pharmaceutical combination is at least about 10 mg. In yet other embodiments, the amount of morphine present in the pharmaceutical combination is at least about 15 mg. In still other embodiments, the amount of morphine present in the
  • pharmaceutical combination is between about 5 mg and about 160 mg. In certain aspects,
  • the amount of morphine present in the pharmaceutical combination is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 100 mg, about 130 mg, about 150 mg, or about 160 mg.
  • the opioid is oxycodone.
  • the amount of oxycodone present in the pharmaceutical combination is at least about 1 microgram, at least about 2 micrograms, at least about 2.5 micrograms, at least about 4 micrograms, at least about 5 micrograms, at least about 10 micrograms, at least about 20 micrograms, or at least about 50 micrograms.
  • the amount of oxycodone present in the pharmaceutical combination is about 1 microgram, about 2 micrograms, about 2.5 micrograms, about 4 micrograms, about 5 micrograms, about 10 micrograms, about 20 micrograms, or about 50 micrograms.
  • the amount of oxycodone present in the pharmaceutical combination is between about 1 microgram and about 50 micrograms, between about 1 microgram and about 20 micrograms, between about 1 microgram and about 10 micrograms, between about 1 microgram and about 5 micrograms, between about 1 microgram and about 4 micrograms, between about 1 microgram and about 2.5 micrograms, between about 1 microgram and about 2 micrograms, between about 2 micrograms and about 50 micrograms, between about 2 micrograms and about 20 micrograms, between about 2 micrograms and about 10 micrograms, between about 2 micrograms and about 5 micrograms, between about 2 micrograms and about 4
  • micrograms between about 2 micrograms and about 2.5 micrograms, between about 2.5 micrograms and about 50 micrograms, between about 2.5 micrograms and about 20 micrograms, between about 2.5 micrograms and about 10 micrograms, between about 2.5 micrograms and about 5 micrograms, between about 2.5 micrograms and about 4
  • micrograms between about 4 micrograms and about 50 micrograms, between about 4 micrograms and about 20 micrograms, between about 4 micrograms and about 10
  • micrograms between about 4 micrograms and about 5 micrograms, between about 5 micrograms and about 50 micrograms, between about 5 micrograms and about 20
  • micrograms between about 5 micrograms and about 10 micrograms, between about 10 micrograms and about 50 micrograms, between about 10 micrograms and about 20 micrograms, or between about 20 micrograms and about 50 micrograms.
  • the amount of oxycodone present in the pharmaceutical combination is at least about 100 micrograms, at least about 200 micrograms, at least about 300 micrograms, at least about 400 micrograms, at least about 500 micrograms, at least about 700 micrograms, at least about 800 micrograms, or at least about 900 micrograms. In certain embodiments, the amount of oxycodone present in the pharmaceutical combination is at least about 100 micrograms, at least about 400 micrograms, at least about 700 micrograms, at least about 800 micrograms, or at least about 900 micrograms.
  • the amount of oxycodone present in the pharmaceutical combination is at least about 100 micrograms, at least about 300 micrograms, at least about 500 micrograms, at least about 700 micrograms, or at least about 900 micrograms. In yet other embodiments, the amount of oxycodone present in the pharmaceutical combination is at least about 200 micrograms, at least about 400 micrograms, at least about 600 micrograms, or at least about 800 micrograms. In some embodiments, the amount of oxycodone present in the pharmaceutical combination is at least about 100 micrograms, at least about 500 micrograms, or at least about 900 micrograms.
  • the amount of oxycodone present in the pharmaceutical combination is about 100 micrograms, about 200 micrograms, about 300 micrograms, about 400 micrograms, about 500 micrograms, about 700 micrograms, about 800 micrograms, or about 900 micrograms. In certain embodiments, the amount of oxycodone present in the pharmaceutical combination is about 100 micrograms, about 400 micrograms, about 700 micrograms, about 800 micrograms, or about 900 micrograms. In other embodiments, the amount of oxycodone present in the pharmaceutical combination is about 100 micrograms, about 300 micrograms, about 500 micrograms, about 700 micrograms, or about 900 micrograms. In yet other embodiments, the amount of oxycodone present in the
  • the pharmaceutical combination is about 200 micrograms, about 400 micrograms, about 600 micrograms, or about 800 micrograms. In some embodiments, the amount of oxycodone present in the pharmaceutical combination is about 100 micrograms, about 500 micrograms, or about 900 micrograms.
  • the amount of oxycodone present in the pharmaceutical combination is between about 100 micrograms and about 900 micrograms, between about 100 micrograms and about 800 micrograms, between about 100 micrograms and about 700 micrograms, between about 100 micrograms and about 600 micrograms, between about 100 micrograms and about 500 micrograms, between about 100 micrograms and about 400 micrograms, between about 100 micrograms and about 300 micrograms, between about 100 micrograms and about 200 micrograms, between about 200 micrograms and about 900 micrograms, between about 200 micrograms and about 800 micrograms, between about 200 micrograms and about 700 micrograms, between about 200 micrograms and about 600 micrograms, between about 200 micrograms and about 500 micrograms, between about 200 micrograms and about 400 micrograms, between about 200 micrograms and about 300 micrograms, between about 300 micrograms and about 900 micrograms, between about 300 micrograms and about 800 micrograms, between about 300 micrograms and about 700 micrograms, between about 100
  • micrograms and about 900 micrograms.
  • the amount of oxycodone present in the pharmaceutical combination is at least about 1 mg, at least about 2 mg, at least about 3 mg, at least about 4 mg, at least about 5 mg, at least about 6 mg, at least about 7 mg, at least about 8 mg, at least about 9 mg, at least about 10 mg, at least about 11 mg, at least about 12 mg, at least about 13 mg, at least about 14 mg, at least about 15 mg, at least about 17 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, at least about
  • the amount of oxycodone present in the pharmaceutical combination is about 1 mg, about 1.25 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 7.5 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 17 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 64 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, or about 1200 mg.
  • the amount of oxycodone present in the pharmaceutical combination is between about 1 mg and about 1200 mg, between about 1 mg and about 1100 mg, between about 1 mg and about 1000 mg, between about 1 mg and about 900 mg, between about 1 mg and about 800 mg, between about 1 mg and about 700 mg, between about 1 mg and about 600 mg, between about 1 mg and about 500 mg, between about 1 mg and about 450 mg, between about 1 mg and about 400 mg, between about 1 mg and about 350 mg, between about 1 mg and about 300 mg, between about 1 mg and about 250 mg, between about 1 mg and about 200 mg, between about 1 mg and about 150 mg, between about 1 mg and about 100 mg, between about 1 mg and about 90 mg, between about 1 mg and about 80 mg, between about 1 mg and about 70 mg, between about 1.25 mg and about 64 mg, between about 1 mg and about 60 mg, between about 1 mg and about 50 mg, between about 1 mg and about 40 mg, between about 1 mg and about 30 mg, between about 1 mg and about 25 mg, between about 1 mg and about
  • the amount of oxycodone present in the pharmaceutical combination is at least about 1 mg, at least about 2 mg, at least about 2.5 mg, at least about 4 mg, at least about 5 mg, at least about 7.5 mg, at least about 8 mg, at least about 10 mg, at least about 15 mg, or at least about 30 mg. In certain embodiments, the amount of oxycodone present in the pharmaceutical combination is between about 1 mg and about 5 mg, between about 1 and about 8 mg, between about 5 mg and about 15 mg, or between about 7.5 mg and about 30 mg. In yet other embodiments, the amount of oxycodone present in the pharmaceutical combination is between about 1.25 mg and about 64 mg.
  • the amount of oxycodone present in the pharmaceutical combination is about 1.25 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 60 mg, or about 64 mg.
  • the opioid is methadone.
  • the amount of methadone present in the pharmaceutical combination is at least about 1 microgram, at least about 2 micrograms, at least about 2.5 micrograms, at least about 4 micrograms, at least about 5 micrograms, at least about 10 micrograms, at least about 20 micrograms, or at least about 50 micrograms. In certain embodiments, the amount of methadone present in the pharmaceutical combination is about 1 microgram, about 2 micrograms, about 2.5 micrograms, about 4 micrograms, about 5 micrograms, about 10 micrograms, about 20 micrograms, or about 50 micrograms.
  • the amount of methadone present in the pharmaceutical combination is between about 1 microgram and about 50 micrograms, between about 1 microgram and about 20 micrograms, between about 1 microgram and about 10 micrograms, between about 1 microgram and about 5 micrograms, between about 1 microgram and about 4 micrograms, between about 1 microgram and about 2.5 micrograms, between about 1 microgram and about 2 micrograms, between about 2 micrograms and about 50 micrograms, between about 2 micrograms and about 20 micrograms, between about 2 micrograms and about 10 micrograms, between about 2 micrograms and about 5 micrograms, between about 2 micrograms and about 4
  • micrograms between about 2 micrograms and about 2.5 micrograms, between about 2.5 micrograms and about 50 micrograms, between about 2.5 micrograms and about 20 micrograms, between about 2.5 micrograms and about 10 micrograms, between about 2.5 micrograms and about 5 micrograms, between about 2.5 micrograms and about 4
  • micrograms between about 4 micrograms and about 50 micrograms, between about 4 micrograms and about 20 micrograms, between about 4 micrograms and about 10
  • micrograms between about 4 micrograms and about 5 micrograms, between about 5 micrograms and about 50 micrograms, between about 5 micrograms and about 20
  • micrograms between about 5 micrograms and about 10 micrograms, between about 10 micrograms and about 50 micrograms, between about 10 micrograms and about 20 micrograms, or between about 20 micrograms and about 50 micrograms.
  • the amount of methadone present in the pharmaceutical combination is at least about 100 micrograms, at least about 200 micrograms, at least about 300 micrograms, at least about 400 micrograms, at least about 500 micrograms, at least about 700 micrograms, at least about 800 micrograms, or at least about 900 micrograms. In certain embodiments, the amount of methadone present in the pharmaceutical combination is at least about 100 micrograms, at least about 400 micrograms, at least about 700 micrograms, at least about 800 micrograms, or at least about 900 micrograms.
  • the amount of methadone present in the pharmaceutical combination is at least about 100 micrograms, at least about 300 micrograms, at least about 500 micrograms, at least about 700 micrograms, or at least about 900 micrograms. In yet other embodiments, the amount of methadone present in the pharmaceutical combination is at least about 200 micrograms, at least about 400 micrograms, at least about 600 micrograms, or at least about 800 micrograms. In some embodiments, the amount of methadone present in the pharmaceutical combination is at least about 100 micrograms, at least about 500 micrograms, or at least about 900 micrograms.
  • the amount of methadone present in the pharmaceutical combination is about 100 micrograms, about 200 micrograms, about 300 micrograms, about 400 micrograms, about 500 micrograms, about 700 micrograms, about 800 micrograms, or about 900 micrograms. In certain embodiments, the amount of methadone present in the pharmaceutical combination is about 100 micrograms, about 400 micrograms, about 700 micrograms, about 800 micrograms, or about 900 micrograms. In other embodiments, the amount of methadone present in the pharmaceutical combination is about 100 micrograms, about 300 micrograms, about 500 micrograms, about 700 micrograms, or about 900 micrograms. In yet other embodiments, the amount of methadone present in the
  • the pharmaceutical combination is about 200 micrograms, about 400 micrograms, about 600 micrograms, or about 800 micrograms. In some embodiments, the amount of methadone present in the pharmaceutical combination is about 100 micrograms, about 500 micrograms, or about 900 micrograms.
  • the amount of methadone present in the pharmaceutical combination is between about 100 micrograms and about 900 micrograms, between about 100 micrograms and about 800 micrograms, between about 100 micrograms and about 700 micrograms, between about 100 micrograms and about 600 micrograms, between about 100 micrograms and about 500 micrograms, between about 100 micrograms and about 400 micrograms, between about 100 micrograms and about 300 micrograms, between about 100 micrograms and about 200 micrograms, between about 200 micrograms and about 900 micrograms, between about 200 micrograms and about 800 micrograms, between about 200 micrograms and about 700 micrograms, between about 200 micrograms and about 600 micrograms, between about 200 micrograms and about 500 micrograms, between about 200 micrograms and about 400 micrograms, between about 200 micrograms and about 300 micrograms, between about 300 micrograms and about 900 micrograms, between about 300 micrograms and about 800 micrograms, between about 300 micrograms and about 700 micrograms, between about 100 microgram
  • the amount of methadone present in the pharmaceutical combination is at least about 1 mg, at least about 2 mg, at least about 3 mg, at least about 4 mg, at least about 5 mg, at least about 6 mg, at least about 7 mg, at least about 8 mg, at least about 9 mg, at least about 10 mg, at least about 11 mg, at least about 12 mg, at least about 13 mg, at least about 14 mg, at least about 15 mg, at least about 17 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, at least about 100 mg, at least about 150 mg, at least about 200 mg, at least about 250 mg, at least about 300 mg, at least about 400 mg, at least about 450 mg, at least about 500 mg, at least about 600 mg, at least about 700 mg, at least about 800 mg, at least about 900 mg, at least about 1000 mg, at least about 1
  • the amount of methadone present in the pharmaceutical combination is about 1 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 17 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, or about 1200 mg.
  • the amount of methadone present in the pharmaceutical combination is about 2.5 mg, about 5 mg, about 10 mg, or about 40 mg. In other embodiments, the amount of methadone present in the pharmaceutical combination is between about 1 mg and about 1200 mg, between about 1 mg and about 1100 mg, between about 1 mg and about 1000 mg, between about 1 mg and about 900 mg, between about 1 mg and about 800 mg, between about 1 mg and about 700 mg, between about 1 mg and about 600 mg, between about 1 mg and about 500 mg, between about 1 mg and about 450 mg, between about 1 mg and about 400 mg, between about 1 mg and about 350 mg, between about 1 mg and about 300 mg, between about 1 mg and about 250 mg, between about 1 mg and about 200 mg, between about 1 mg and about 150 mg, between about 1 mg and about 100 mg, between about 1 mg and about 90 mg, between about 1 mg and about 80 mg, between about 1 mg and about 70 mg, between about 1 mg and about 60 mg, between about 1 mg and about 50 mg, between about 1 mg and about 40 mg, between about
  • the amount of methadone present in the pharmaceutical combination is at least about 1 mg, at least about 2 mg, at least about 2.5 mg, at least about 4 mg, at least about 5 mg, at least about 7.5 mg, at least about 8 mg, at least about 10 mg, at least about 15 mg, or at least about 30 mg. In certain embodiments, the amount of methadone present in the pharmaceutical combination is between about 1 mg and about 5 mg, between about 1 and about 8 mg, between about 5 mg and about 15 mg, or between about 7.5 mg and about 30 mg. In yet other embodiments, the amount of methadone present in the pharmaceutical combination is between about 2.5 mg and about 8 mg. In certain embodiments, the amount of methadone present in the pharmaceutical combination is about 2.5 mg, about 5 mg, or about 8 mg.
  • the opioid is hydromorphone.
  • the amount of hydromorphone present in the pharmaceutical combination is at least about 1 microgram, at least about 2 micrograms, at least about 2.5 micrograms, at least about 4 micrograms, at least about 5 micrograms, at least about 10 micrograms, at least about 20 micrograms, or at least about 50 micrograms. In certain embodiments, the amount of hydromorphone present in the pharmaceutical combination is about 1 microgram, about 2 micrograms, about 2.5 micrograms, about 4 micrograms, about 5 micrograms, about 10 micrograms, about 20 micrograms, or about 50 micrograms.
  • the amount of hydromorphone present in the pharmaceutical combination is between about 1 microgram and about 50 micrograms, between about 1 microgram and about 20 micrograms, between about 1 microgram and about 10 micrograms, between about 1 microgram and about 5 micrograms, between about 1 microgram and about 4 micrograms, between about 1 microgram and about 2.5 micrograms, between about 1 microgram and about 2 micrograms, between about 2 micrograms and about 50 micrograms, between about 2 micrograms and about 20 micrograms, between about 2 micrograms and about 10
  • micrograms between about 2 micrograms and about 5 micrograms, between about 2 micrograms and about 4 micrograms, between about 2 micrograms and about 2.5
  • micrograms between about 2.5 micrograms and about 50 micrograms, between about 2.5 micrograms and about 20 micrograms, between about 2.5 micrograms and about 10 micrograms, between about 2.5 micrograms and about 5 micrograms, between about 2.5 micrograms and about 4 micrograms, between about 4 micrograms and about 50 micrograms, between about 4 micrograms and about 20 micrograms, between about 4 micrograms and about 10 micrograms, between about 4 micrograms and about 5 micrograms, between about 5 micrograms and about 50 micrograms, between about 5 micrograms and about 20
  • micrograms between about 5 micrograms and about 10 micrograms, between about 10 micrograms and about 50 micrograms, between about 10 micrograms and about 20 micrograms, or between about 20 micrograms and about 50 micrograms.
  • the pharmaceutical combination is at least about 100 micrograms, at least about 200 micrograms, at least about 300 micrograms, at least about 400 micrograms, at least about 500 micrograms, at least about 700 micrograms, at least about 800 micrograms, or at least about 900 micrograms.
  • the amount of hydromorphone present in the pharmaceutical combination is at least about 100 micrograms, at least about 400 micrograms, at least about 700 micrograms, at least about 800 micrograms, or at least about 900 micrograms. In other embodiments, the amount of hydromorphone present in the
  • the pharmaceutical combination is at least about 100 micrograms, at least about 300 micrograms, at least about 500 micrograms, at least about 700 micrograms, or at least about 900 micrograms. In yet other embodiments, the amount of hydromorphone present in the pharmaceutical combination is at least about 200 micrograms, at least about 400 micrograms, at least about 600 micrograms, or at least about 800 micrograms. In some embodiments, the amount of hydromorphone present in the pharmaceutical combination is at least about 100 micrograms, at least about 500 micrograms, or at least about 900 micrograms.
  • the pharmaceutical combination is about 100 micrograms, about 200 micrograms, about 300 micrograms, about 400 micrograms, about 500 micrograms, about 700 micrograms, about 800 micrograms, or about 900 micrograms.
  • the amount of hydromorphone present in the pharmaceutical combination is about 100 micrograms, about 400 micrograms, about 700 micrograms, about 800 micrograms, or about 900 micrograms. In other embodiments, the amount of hydromorphone present in the pharmaceutical
  • the combination is about 100 micrograms, about 300 micrograms, about 500 micrograms, about 700 micrograms, or about 900 micrograms. In yet other embodiments, the amount of hydromorphone present in the pharmaceutical combination is about 200 micrograms, about 400 micrograms, about 600 micrograms, or about 800 micrograms. In some embodiments, the amount of hydromorphone present in the pharmaceutical combination is about 100 micrograms, about 500 micrograms, or about 900 micrograms.
  • the amount of hydromorphone present in the pharmaceutical combination is between about 100 micrograms and about 900 micrograms, between about 100 micrograms and about 800 micrograms, between about 100 micrograms and about 700 micrograms, between about 100 micrograms and about 600 micrograms, between about 100 micrograms and about 500 micrograms, between about 100 micrograms and about 400 micrograms, between about 100 micrograms and about 300 micrograms, between about 100 micrograms and about 200 micrograms, between about 200 micrograms and about 900 micrograms, between about 200 micrograms and about 800 micrograms, between about 200 micrograms and about 700 micrograms, between about 200 micrograms and about 600 micrograms, between about 200 micrograms and about 500 micrograms, between about 200 micrograms and about 400 micrograms, between about 200 micrograms and about 300 micrograms, between about 300 micrograms and about 900 micrograms, between about 300 micrograms and about 800 micrograms, between about 300 micrograms and about 700 micrograms, between about 100 microgram
  • pharmaceutical combination is at least about 1 mg, at least about 2 mg, at least about 3 mg, at least about 4 mg, at least about 5 mg, at least about 6 mg, at least about 7 mg, at least about 8 mg, at least about 9 mg, at least about 10 mg, at least about 11 mg, at least about 12 mg, at least about 13 mg, at least about 14 mg, at least about 15 mg, at least about 17 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, at least about 100 mg, at least about 150 mg, at least about 200 mg, at least about 250 mg, at least about 300 mg, at least about 400 mg, at least about 450 mg, at least about 500 mg, at least about 600 mg, at least about 700 mg, at least about 800 mg, at least about 900 mg, at least about 1000 mg, at least about 1100 mg, or at least about 1200 mg.
  • the amount of hydromorphone present in the pharmaceutical combination is about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 20 mg, about 25 mg, about 25.6 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, or about 1200 mg. In other embodiments, the amount of hydromorphone present in the pharmaceutical
  • combination is between about 1 mg and about 1200 mg, between about 1 mg and about 1100 mg, between about 1 mg and about 1000 mg, between about 1 mg and about 900 mg, between about 1 mg and about 800 mg, between about 1 mg and about 700 mg, between about 1 mg and about 600 mg, between about 1 mg and about 500 mg, between about 1 mg and about 450 mg, between about 1 mg and about 400 mg, between about 1 mg and about 350 mg, between about 1 mg and about 300 mg, between about 1 mg and about 250 mg, between about 1 mg and about 200 mg, between about 1 mg and about 150 mg, between about 1 mg and about 100 mg, between about 1 mg and about 90 mg, between about 1 mg and about 80 mg, between about 1 mg and about 70 mg, between about 1 mg and about 60 mg, between about 1 mg and about 50 mg, between about 1 mg and about 40 mg, between about 1 mg and about 30 mg, between about 1 mg and about 25.6 mg, between about 1 mg and about 25 mg, between about 1 mg and about 20 mg, between about 1 mg and about 15 mg, between about 1 mg
  • the amount of hydromorphone present in the pharmaceutical combination is at least about 1 mg, at least about 2 mg, at least about 2.5 mg, at least about 4 mg, at least about 5 mg, at least about 7.5 mg, at least about 8 mg, at least about 10 mg, at least about 15 mg, at least about 20 mg, or at least about 30 mg. In certain embodiments, the amount of hydromorphone present in the pharmaceutical combination is between about 1 mg and about 5 mg, between about 1 and about 8 mg, between about 5 mg and about 15 mg, between about 7.5 mg and about 30 mg, or between about 1 mg and about 30 mg. In still other embodiments, the amount of hydromorphone present in the pharmaceutical
  • the combination is between about 1 mg and about 25. 6 mg.
  • the amount of hydromorphone present in the pharmaceutical combination is about 1 mg, about 2 mg, about 4 mg, about 8 mg, about 12 mg , about 16 mg, or about 25.6 mg.
  • the opioid is oxymorphone.
  • the amount of oxymorphone present in the pharmaceutical combination is at least about 1 microgram, at least about 2 micrograms, at least about 2.5 micrograms, at least about 4 micrograms, at least about 5 micrograms, at least about 10 micrograms, at least about 20 micrograms, or at least about 50 micrograms.
  • the amount of oxymorphone present in the pharmaceutical combination is about 1 microgram, about 2 micrograms, about 2.5 micrograms, about 4 micrograms, about 5 micrograms, about 10 micrograms, about 20 micrograms, or about 50 micrograms.
  • the amount of oxymorphone present in the pharmaceutical combination is between about 1 microgram and about 50 micrograms, between about 1 microgram and about 20 micrograms, between about 1 microgram and about 10 micrograms, between about 1 microgram and about 5 micrograms, between about 1 microgram and about 4 micrograms, between about 1 microgram and about 2.5 micrograms, between about 1 microgram and about 2 micrograms, between about 2 micrograms and about 50 micrograms, between about 2 micrograms and about 20 micrograms, between about 2 micrograms and about 10 micrograms, between about 2 micrograms and about 5 micrograms, between about 2 micrograms and about 4
  • micrograms between about 2 micrograms and about 2.5 micrograms, between about 2.5 micrograms and about 50 micrograms, between about 2.5 micrograms and about 20 micrograms, between about 2.5 micrograms and about 10 micrograms, between about 2.5 micrograms and about 5 micrograms, between about 2.5 micrograms and about 4
  • micrograms between about 4 micrograms and about 50 micrograms, between about 4 micrograms and about 20 micrograms, between about 4 micrograms and about 10
  • micrograms between about 4 micrograms and about 5 micrograms, between about 5 micrograms and about 50 micrograms, between about 5 micrograms and about 20
  • micrograms between about 5 micrograms and about 10 micrograms, between about 10 micrograms and about 50 micrograms, between about 10 micrograms and about 20 micrograms, or between about 20 micrograms and about 50 micrograms.
  • the amount of oxymorphone present in the pharmaceutical combination is at least about 100 micrograms, at least about 200 micrograms, at least about 300 micrograms, at least about 400 micrograms, at least about 500 micrograms, at least about 700 micrograms, at least about 800 micrograms, or at least about 900 micrograms. In certain embodiments, the amount of oxymorphone present in the pharmaceutical combination is at least about 100 micrograms, at least about 400 micrograms, at least about 700 micrograms, at least about 800 micrograms, or at least about 900 micrograms.
  • the amount of oxymorphone present in the pharmaceutical combination is at least about 100 micrograms, at least about 300 micrograms, at least about 500 micrograms, at least about 700 micrograms, or at least about 900 micrograms. In yet other embodiments, the amount of oxymorphone present in the pharmaceutical combination is at least about 200 micrograms, at least about 400 micrograms, at least about 600 micrograms, or at least about 800 micrograms. In some embodiments, the amount of oxymorphone present in the pharmaceutical
  • the combination is at least about 100 micrograms, at least about 500 micrograms, or at least about 900 micrograms.
  • the amount of oxymorphone present in the pharmaceutical combination is about 100 micrograms, about 200 micrograms, about 300 micrograms, about 400 micrograms, about 500 micrograms, about 700 micrograms, about 800 micrograms, or about 900 micrograms.
  • the amount of oxymorphone present in the pharmaceutical combination is about 100 micrograms, about 400 micrograms, about 700 micrograms, about 800 micrograms, or about 900 micrograms.
  • the amount of oxymorphone present in the pharmaceutical combination is about 100 micrograms, about 300 micrograms, about 500 micrograms, about 700 micrograms, or about 900 micrograms. In yet other embodiments, the amount of oxymorphone present in the pharmaceutical combination is about 200 micrograms, about 400 micrograms, about 600 micrograms, or about 800 micrograms. In some embodiments, the amount of oxymorphone present in the pharmaceutical combination is about 100 micrograms, about 500 micrograms, or about 900 micrograms.
  • the amount of oxymorphone present in the pharmaceutical combination is between about 100 micrograms and about 900 micrograms, between about 100 micrograms and about 800 micrograms, between about 100 micrograms and about 700 micrograms, between about 100 micrograms and about 600 micrograms, between about 100 micrograms and about 500 micrograms, between about 100 micrograms and about 400 micrograms, between about 100 micrograms and about 300 micrograms, between about 100 micrograms and about 200 micrograms, between about 200 micrograms and about 900 micrograms, between about 200 micrograms and about 800 micrograms, between about 200 micrograms and about 700 micrograms, between about 200 micrograms and about 600 micrograms, between about 200 micrograms and about 500 micrograms, between about 200 micrograms and about 400 micrograms, between about 200 micrograms and about 300 micrograms, between about 300 micrograms and about 900 micrograms, between about 300 micrograms and about 800 micrograms, between about 300 micrograms and about 700 micrograms, between about 100 micro
  • micrograms and about 900 micrograms.
  • the amount of oxymorphone present in the pharmaceutical combination is at least about 1 mg, at least about 2 mg, at least about 3 mg, at least about 4 mg, at least about 5 mg, at least about 6 mg, at least about 7 mg, at least about 8 mg, at least about 9 mg, at least about 10 mg, at least about 11 mg, at least about 12 mg, at least about 13 mg, at least about 14 mg, at least about 15 mg, at least about 17 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, at least about
  • the amount of oxymorphone present in the pharmaceutical combination is about 1 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 7.5 mg about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 17 mg, about 20 mg, about 25 mg, about 30 mg, about 32 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, or about 1200 mg.
  • the amount of oxymorphone present in the pharmaceutical combination is between about 1 mg and about 1200 mg, between about 1 mg and about 1100 mg, between about 1 mg and about 1000 mg, between about 1 mg and about 900 mg, between about 1 mg and about 800 mg, between about 1 mg and about 700 mg, between about 1 mg and about 600 mg, between about 1 mg and about 500 mg, between about 1 mg and about 450 mg, between about 1 mg and about 400 mg, between about 1 mg and about 350 mg, between about 1 mg and about 300 mg, between about 1 mg and about 250 mg, between about 1 mg and about 200 mg, between about 1 mg and about 150 mg, between about 1 mg and about 100 mg, between about 1 mg and about 90 mg, between about 1 mg and about 80 mg, between about 1 mg and about 70 mg, between about 1 mg and about 60 mg, between about 1 mg and about 50 mg, between about 1 mg and about 40 mg, between about 1 mg and about 30 mg, between about 1 mg and about 25 mg, between about 1 mg and about 20 mg, between about 1 mg and about 15 mg
  • the amount of oxymorphone present in the pharmaceutical combination is at least about 1 mg, at least about 2 mg, at least about 2.5 mg, at least about 4 mg, at least about 5 mg, at least about 7.5 mg, at least about 8 mg, at least about 10 mg, at least about 15 mg, or at least about 30 mg. In certain embodiments, the amount of oxymorphone present in the pharmaceutical combination is between about 1 mg and about 5 mg, between about 1 and about 8 mg, between about 5 mg and about 15 mg, between about 7.5 mg and about 30 mg, or between about 2.5 mg and about 32 mg. In other embodiments, the amount of oxymorphone present in the pharmaceutical combination is about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, or about 32 mg.
  • the opioid is tramadol.
  • the amount of tramadol present in the pharmaceutical combination is at least about 1 microgram, at least about 2 micrograms, at least about 2.5 micrograms, at least about 4 micrograms, at least about 5 micrograms, at least about 10 micrograms, at least about 20 micrograms, or at least about 50 micrograms. In certain embodiments, the amount of tramadol present in the pharmaceutical combination is about 1 microgram, about 2 micrograms, about 2.5 micrograms, about 4 micrograms, about 5 micrograms, about 10 micrograms, about 20 micrograms, or about 50 micrograms.
  • the amount of tramadol present in the pharmaceutical combination is between about 1 microgram and about 50 micrograms, between about 1 microgram and about 20 micrograms, between about 1 microgram and about 10 micrograms, between about 1 microgram and about 5 micrograms, between about 1 microgram and about 4 micrograms, between about 1 microgram and about 2.5 micrograms, between about 1 microgram and about 2 micrograms, between about 2 micrograms and about 50 micrograms, between about 2 micrograms and about 20 micrograms, between about 2 micrograms and about 10 micrograms, between about 2 micrograms and about 5 micrograms, between about 2 micrograms and about 4
  • micrograms between about 2 micrograms and about 2.5 micrograms, between about 2.5 micrograms and about 50 micrograms, between about 2.5 micrograms and about 20 micrograms, between about 2.5 micrograms and about 10 micrograms, between about 2.5 micrograms and about 5 micrograms, between about 2.5 micrograms and about 4
  • micrograms between about 4 micrograms and about 50 micrograms, between about 4 micrograms and about 20 micrograms, between about 4 micrograms and about 10 micrograms, between about 4 micrograms and about 5 micrograms, between about 5 micrograms and about 50 micrograms, between about 5 micrograms and about 20
  • micrograms between about 5 micrograms and about 10 micrograms, between about 10 micrograms and about 50 micrograms, between about 10 micrograms and about 20 micrograms, or between about 20 micrograms and about 50 micrograms.
  • the amount of tramadol present in the pharmaceutical combination is at least about 100 micrograms, at least about 200 micrograms, at least about 300 micrograms, at least about 400 micrograms, at least about 500 micrograms, at least about 700 micrograms, at least about 800 micrograms, or at least about 900 micrograms. In certain embodiments, the amount of tramadol present in the pharmaceutical combination is at least about 100 micrograms, at least about 400 micrograms, at least about 700 micrograms, at least about 800 micrograms, or at least about 900 micrograms.
  • the amount of tramadol present in the pharmaceutical combination is at least about 100 micrograms, at least about 300 micrograms, at least about 500 micrograms, at least about 700 micrograms, or at least about 900 micrograms. In yet other embodiments, the amount of tramadol present in the pharmaceutical combination is at least about 200 micrograms, at least about 400 micrograms, at least about 600 micrograms, or at least about 800 micrograms. In some embodiments, the amount of tramadol present in the pharmaceutical combination is at least about 100 micrograms, at least about 500 micrograms, or at least about 900 micrograms.
  • the amount of tramadol present in the pharmaceutical combination is about 100 micrograms, about 200 micrograms, about 300 micrograms, about 400 micrograms, about 500 micrograms, about 700 micrograms, about 800 micrograms, or about 900 micrograms. In certain embodiments, the amount of tramadol present in the pharmaceutical combination is about 100 micrograms, about 400 micrograms, about 700 micrograms, about 800 micrograms, or about 900 micrograms. In other embodiments, the amount of tramadol present in the pharmaceutical combination is about 100 micrograms, about 300 micrograms, about 500 micrograms, about 700 micrograms, or about 900 micrograms.
  • the amount of tramadol present in the pharmaceutical combination is about 200 micrograms, about 400 micrograms, about 600 micrograms, or about 800 micrograms. In some embodiments, the amount of tramadol present in the pharmaceutical combination is about 100 micrograms, about 500 micrograms, or about 900 micrograms.
  • the amount of tramadol present in the pharmaceutical combination is between about 100 micrograms and about 900 micrograms, between about 100 micrograms and about 800 micrograms, between about 100 micrograms and about 700 micrograms, between about 100 micrograms and about 600 micrograms, between about 100 micrograms and about 500 micrograms, between about 100 micrograms and about 400 micrograms, between about 100 micrograms and about 300 micrograms, between about 100 micrograms and about 200 micrograms, between about 200 micrograms and about 900 micrograms, between about 200 micrograms and about 800 micrograms, between about 200 micrograms and about 700 micrograms, between about 200 micrograms and about 600 micrograms, between about 200 micrograms and about 500 micrograms, between about 200 micrograms and about 400 micrograms, between about 200 micrograms and about 300 micrograms, between about 300 micrograms and about 900 micrograms, between about 300 micrograms and about 800 micrograms, between about 300 micrograms and about 700 micrograms, between about 100
  • the amount of tramadol present in the pharmaceutical combination is at least about 1 mg, at least about 2 mg, at least about 3 mg, at least about 4 mg, at least about 5 mg, at least about 6 mg, at least about 7 mg, at least about 8 mg, at least about 9 mg, at least about 10 mg, at least about 11 mg, at least about 12 mg, at least about 13 mg, at least about 14 mg, at least about 15 mg, at least about 17 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, at least about 100 mg, at least about 150 mg, at least about 200 mg, at least about 250 mg, at least about 300 mg, at least about 400 mg, at least about 450 mg, at least about 500 mg, at least about 600 mg, at least about 700 mg, at least about 800 mg, at least about 900 mg, at least about 1000 mg, at least
  • the amount of tramadol present in the pharmaceutical combination is about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 17 mg, about 18.75 mg, about 20 mg, about 25 mg, about 30 mg, about 37.5 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 240 mg, about 250 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, or about 1200 mg. In other embodiments, the amount of tramadol present in the pharmaceutical
  • combination is between about 1 mg and about 1200 mg, between about 1 mg and about 1100 mg, between about 1 mg and about 1000 mg, between about 1 mg and about 900 mg, between about 1 mg and about 800 mg, between about 1 mg and about 700 mg, between about 1 mg and about 600 mg, between about 1 mg and about 500 mg, between about 1 mg and about 450 mg, between about 1 mg and about 400 mg, between about 1 mg and about 350 mg, between about 1 mg and about 300 mg, between about 1 mg and about 250 mg, between about 1 mg and about 200 mg, between about 1 mg and about 150 mg, between about 1 mg and about 100 mg, between about 1 mg and about 90 mg, between about 1 mg and about 80 mg, between about 1 mg and about 70 mg, between about 1 mg and about 60 mg, between about 1 mg and about 50 mg, between about 1 mg and about 40 mg, between about 1 mg and about 30 mg, between about 1 mg and about 25 mg, between about 1 mg and about 20 mg, between about 1 mg and about 15 mg, between about 1 mg and about 14 mg, between about 1 mg and
  • the amount of tramadol present in the pharmaceutical combination is at least about 1 mg, at least about 2 mg, at least about 2.5 mg, at least about 4 mg, at least about 5 mg, at least about 7.5 mg, at least about 8 mg, at least about 10 mg, at least about 15 mg, or at least about 30 mg.
  • the amount of tramadol present in the pharmaceutical combination is between about 1 mg and about 5 mg, between about 1 and about 8 mg, between about 5 mg and about 15 mg, between about 7.5 mg and about 30 mg, or between about 15 mg and about 250 mg.
  • the amount of tramadol present in the pharmaceutical combination is between about 18.75 mg and about 240 mg. In other embodiments, the amount of tramadol present is about 18.75 mg, about 37.5 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, or about 240 mg.
  • Non-Opioid Analgesic and Other Active Agents
  • other active agents may be co-administered with the cannabinoid and opioid or provided in the same fixed-dose combination form with the opioid and/or cannabinoid to provide further pain relief or relief of pain-related symptoms.
  • pharmaceutical combinations comprising a cannabinoid, an opioid, and one or more other active agents.
  • the one or more other active agents are selected from the group consisting of a non-opioid analgesic, a sedative, or any combination thereof.
  • the present disclosure provides a pharmaceutical combination comprising a cannabinoid, an opioid, and a non-opioid analgesic.
  • the pharmaceutical combination comprises a non-opioid analgesic selected from the group consisting of acetaminophen, aspirin, and ibuprofen.
  • the amount of non-opioid analgesic present in the pharmaceutical combination is about 100 mg, 150 mg, about 200 mg, about 250 mg, about 300 mg, 325 mg, about 350 mg, about 400 mg, about 500 mg, about 650 mg or about 750 mg. In certain embodiments, the amount of non-opioid analgesic present in the
  • pharmaceutical combination is between about 100 mg and about 750 mg.
  • the non-opioid analgesic is acetaminophen. In certain embodiments wherein the non-opioid analgesic is acetaminophen, the amount of
  • acetaminophen present in the pharmaceutical combination is about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, 325 mg, about 350 mg, about 400 mg, about 500 mg, about 650 mg, or about 750 mg. In certain embodiments, the amount of acetaminophen present in the pharmaceutical combination is between about 100 mg and about 750 mg. In other embodiments, the amount of acetaminophen present in the pharmaceutical combination is about 300 mg, about 325 mg, 400 mg, about 500 mg, about 650 mg, or about 750 mg.
  • the non-opioid analgesic is aspirin. In certain embodiments wherein the non-opioid analgesic is aspirin, the amount of aspirin present in the
  • the pharmaceutical combination is about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 325 mg, about 350 mg, about 400 mg, about 500 mg, about 650 mg, or about 750 mg.
  • the amount of aspirin present in the pharmaceutical combination is between about 100 mg and about 750 mg. In other embodiments, the amount of aspirin present in the pharmaceutical combination is about 325 mg.
  • the non-opioid analgesic is ibuprofen. In certain
  • the amount of ibuprofen present in the pharmaceutical combination is about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 325 mg, about 350 mg, about 400 mg, about 500 mg, about 650 mg, or about 750 mg. In certain embodiments, the amount of ibuprofen present in the
  • pharmaceutical combination is between about 100 mg and about 750 mg.
  • the amount of ibuprofen present in the pharmaceutical combination is about 200 mg, or about 300 mg, about 325 mg, or about 400 mg.
  • the cannabinoid, the opioid, and the non-opioid analgesic may be administered in two or three individual dosage forms.
  • the cannabinoid, the opioid, and non-opioid analgesic are administered in two dosage forms, two of the cannabinoid, opioid, and non-opioid analgesic may be administered in single dosage form and the third administered in an individual dosage form.
  • the opioid and non-opioid analgesic are provided together in a first dosage form and the cannabinoid is provided in a second individual dosage form.
  • the pharmaceutical combination is a fixed-dose combination
  • the cannabinoid, the opioid and the non-opioid analgesic are combined in a single fixed dosage form.
  • provided herein are pharmaceutical combinations comprising a cannabinoid, an opioid, and a sedative.
  • pharmaceutical combinations comprising a cannabinoid, an opioid, a non-opioid analgesic, and a sedative.
  • the pharmaceutical combination comprises a sedative
  • the sedative is a barbiturate or a benzodiazepine.
  • the sedative is a barbiturate. In certain embodiments wherein the sedative is a barbiturate the sedative is selected from the group consisting of secobarbital, phenobarbital, and butalbital. In certain embodiments, the sedative is butalbital. In some embodiments wherein the sedative is butalbital, the amount of butalbital present in the pharmaceutical combination is about 25 mg or about 50 mg. In other embodiments wherein the sedative is secobarbital, the amount of secobarbital present in the pharmaceutical combination is about 30 mg, about 50 mg or about 100 mg.
  • the sedative is selected from the group consisting of diazepam, alprazolam, lorazepam, and clonazepam.
  • the amount of alprazolam, lorazepam or clonazepam present in the pharmaceutical combination is between about 0.1 mg and about 3 mg.
  • the amount of diazepam present in the pharmaceutical combination is between about 2 mg and about 10 mg.
  • the cannabinoid, the opioid, and the other active agents may be administered in two or three individual dosage forms.
  • the cannabinoid, the opioid, and sedative are administered in two dosage forms
  • two of the cannabinoid, opioid, and sedative may be administered in single dosage form and the third administered in an individual dosage form.
  • the opioid and sedative are provided together in a first dosage form and the cannabinoid is provided in a second individual dosage form.
  • the pharmaceutical combination is a fixed-dose combination
  • the cannabinoid, the opioid and the sedative are combined in a single fixed dosage form.
  • the pharmaceutical combination comprises a non-opioid analgesic and a sedative
  • the cannabinoid, the opioid, the non-opioid analgesic, and the sedative may be administered in as many as one, two, three or four individual dosage forms.
  • opioids and non-opioid analgesics and/or other active agents may be especially effective when co-administered with or provided in a single fixed- dose combination formulation with cannabinoids.
  • the pharmaceutical combination comprises buprenorphine and a non-opioid analgesic selected from the group consisting of acetaminophen, ibuprofen, and aspirin. In certain embodiments, the pharmaceutical combination comprises
  • the pharmaceutical combination comprises buprenorphine and acetaminophen.
  • the pharmaceutical combination comprises buprenorphine and ibuprofen.
  • the pharmaceutical combination comprises buprenorphine and aspirin.
  • the pharmaceutical combination comprises codeine and a non-opioid analgesic selected from the group consisting of acetaminophen, ibuprofen, and aspirin.
  • the pharmaceutical combination comprises codeine and acetaminophen.
  • the pharmaceutical combination comprises codeine and ibuprofen.
  • the pharmaceutical combination comprises codeine and aspirin.
  • the pharmaceutical combination comprises morphine and a non-opioid analgesic selected from the group consisting of acetaminophen, ibuprofen, and aspirin.
  • the pharmaceutical combination comprises morphine and acetaminophen.
  • the pharmaceutical combination comprises morphine and ibuprofen.
  • the pharmaceutical combination comprises morphine and aspirin.
  • the pharmaceutical combination comprises methadone and a non-opioid analgesic selected from the group consisting of acetaminophen, ibuprofen, and aspirin.
  • the pharmaceutical combination comprises methadone and acetaminophen.
  • the pharmaceutical combination comprises methadone and ibuprofen.
  • the pharmaceutical combination comprises methadone and aspirin.
  • the pharmaceutical combination comprises hydrocodone and a non-opioid analgesic elected from the group consisting of acetaminophen, ibuprofen, and aspirin.
  • the pharmaceutical combination comprises hydrocodone and a non-opioid analgesic, wherein the non-opioid analgesic is acetaminophen or ibuprofen.
  • the pharmaceutical combination comprises hydrocodone and acetaminophen.
  • the pharmaceutical combination comprises hydrocodone and ibuprofen.
  • the pharmaceutical combination comprises hydrocodone and aspirin.
  • the pharmaceutical combination comprises hydromorphone and a non-opioid analgesic elected from the group consisting of acetaminophen, ibuprofen, and aspirin. In certain embodiments, the pharmaceutical combination comprises
  • the pharmaceutical combination comprises hydromorphone and acetaminophen.
  • the pharmaceutical combination comprises hydromorphone and ibuprofen.
  • the pharmaceutical combination comprises hydromorphone and aspirin.
  • the pharmaceutical combination comprises oxycodone and a non-opioid analgesic selected from the group consisting of acetaminophen, aspirin, and ibuprofen.
  • the pharmaceutical combination comprises oxycodone and acetaminophen.
  • the pharmaceutical combination comprises oxycodone and ibuprofen.
  • the pharmaceutical combination comprises oxycodone and aspirin.
  • the pharmaceutical combination comprises oxymorphone and a non-opioid analgesic selected from the group consisting of acetaminophen, aspirin, and ibuprofen.
  • the pharmaceutical combination comprises oxymorphone and acetaminophen.
  • the pharmaceutical combination comprises oxymorphone and ibuprofen.
  • the pharmaceutical combination comprises oxymorphone and aspirin.
  • the pharmaceutical combination comprises tramadol and a non-opioid analgesic selected from the group consisting of acetaminophen, aspirin, and ibuprofen.
  • the pharmaceutical combination comprises tramadol and acetaminophen.
  • the pharmaceutical combination comprises tramadol and ibuprofen.
  • the pharmaceutical combination comprises tramadol and aspirin.
  • the amounts of each active agent— the cannabinoid and/or the opioid— may be lowered substantially from the amounts used for individual administration of the cannabinoid or opioid to achieve an appreciable analgesic effect, an analgesic effect of similar magnitude, an equianalgesic effect, or even a superior analgesic effect.
  • the amount of opioid used for individual administration, or alone, to achieve an analgesic effect may be referred to as the“standard opioid dose”.
  • the“standard opioid dose” may depend upon any number of factors, including but not limited to the condition being treated, the medical history and condition of the subject being treated, the opioid being administered, the opioid etiology, pharmacodynamics, pharmacokinetics, the dosage form and route of administration.
  • the standard opioid dose is the baseline opioid dose administered to a patient in need thereof before initiating pain management by the method disclosed herein.
  • the standard opioid dose is an equianalgesic dose in relation to other opioid dosages.
  • the amount of the active agent in the pharmaceutical combination can be characterized as a therapeutically effective amount or a sub-therapeutic amount.
  • therapeutically effective amount of the cannabinoid or opioid may be defined as an amount sufficient to produce an analgesic effect when said cannabinoid or opioid is administered alone.
  • a sub-therapeutic amount of the cannabinoid or the opioid may be defined as an amount which does not produce an analgesic effect when said cannabinoid or opioid is administered alone.
  • the amount of the opioid present in the pharmaceutical combination is a therapeutically effective amount. In certain embodiments, the amount of the opioid present in the pharmaceutical combination is a sub -therapeutic amount. In other embodiments, the amount of cannabinoid present in the pharmaceutical combination is a therapeutically effective amount. In certain embodiments, the amount of cannabinoid present in the pharmaceutical combination is a sub -therapeutic amount. In some embodiments, the pharmaceutical combination comprises the cannabinoid and the opioid, wherein the amount of cannabinoid present is a therapeutically effective amount and the amount of opioid present is a therapeutically effective amount.
  • the amount of cannabinoid present is a therapeutically effective amount and the amount of opioid present is a sub- therapeutic amount.
  • the pharmaceutical combination comprises the cannabinoid and the opioid, wherein the amount of cannabinoid present is a sub-therapeutic amount and the amount of opioid present is a therapeutically effective amount.
  • the pharmaceutical combination comprises the cannabinoid and the opioid, wherein the amount of cannabinoid present is a sub -therapeutic amount and the amount of opioid present is a sub-therapeutic amount.
  • the present disclosure also provides for a pharmaceutical combination comprising a cannabinoid and an opioid, having an additive or greater than additive (i.e., synergistic) analgesic effect.
  • the pharmaceutical combination as described herein is synergistically effective.
  • the present disclosure provides for a pharmaceutical combination which displays a synergistic analgesic effect, wherein one or both of the cannabinoid and opioid are present in an amount lower than would be required for each active ingredient alone to produce the same, similar, or better analgesic effect.
  • the pharmaceutical combination demonstrates a one-way synergistic effect.
  • the opioid is present in an amount lower than would be required for the opioid alone to produce the same, similar, or better analgesic effect.
  • the opioid is present in an amount lower than would be required for the opioid alone to produce the same, similar, or better analgesic effect.
  • the cannabinoid is present in an amount lower than would be required for the cannabinoid alone to produce the same, similar, or better analgesic effect.
  • the pharmaceutical combination demonstrates a two-way synergistic effect.
  • both the cannabinoid and opioid are present in amounts lower than would be required for the cannabinoid alone and opioid alone to produce the same, similar, or better analgesic effect.
  • the pharmaceutical combination comprises the cannabinoid and the opioid in amounts such that the amount of opioid is at least about 20 percent less, at least about 25 percent less, at least about 30 percent less, at least about 40 percent less, at least 2 times less, at least 5 times less, at least 7 times less, at least 10 times less, at least 12 times less, at least 15 times less, at least 17 times less, at least 20 times less or at least 25 times less than the amount of opioid required to produce the same, similar, or better analgesic effect with the opioid alone.
  • the amount of opioid is at least about 20 percent less, at least about 25 percent less, at least about 30 percent less, at least about 40 percent less, at least 2 times less, at least 7 times less, at least 12 times less, at least 17 times less, or at least 25 times less than the amount of opioid required to produce the same, similar, or better analgesic effect with the opioid alone.
  • the amounts of opioid is between about 20 percent and about 25 percent less, between about 25 percent and about 30 percent less, between about 30 percent and about 40 percent less, between about 40 percent and about 50 percent less, between about 2 times and about 5 times less, between about 5 times and about 10 times less, between about 10 times and about 15 times less, between about 15 times and about 20 times less, or between about 20 times and about 25 times less than the amount of opioid required to produce the same, similar, or better analgesic effect with the opioid alone.
  • the opioid is present in the pharmaceutical combination in an amount that is about 2 percent, about 3 percent, about 4 percent, about 5 percent, about 6 percent, about 7 percent, about 8 percent, about 9 percent, about 10 percent, about 12 percent, about 15 percent, about 17 percent, about 20 percent, about 25 percent, about 30 percent, about 35 percent, about 40 percent, about 45 percent, about 50 percent, about 60 percent, about 70 percent, or about 80 percent of the amount of opioid required to produce the same, similar, or better analgesic effect with the opioid alone.
  • the opioid is present in the pharmaceutical combination in an amount that is between about 2 percent and about 5 percent, between about 5 percent and 10 percent, between about 7 percent and about 10 percent, between about 10 percent and about 15 percent, between about 12 percent and about 15 percent, between about 15 percent and about 20 percent, between about 17 percent and about 20 percent, between about 20 percent and about 50 percent, between about 20 percent and about 40 percent, between about 20 percent and about 30 percent, between about 30 percent and about 40 percent, between about 30 percent and about 50 percent, between about 40 percent and about 60 percent, or between about 60 percent and about 80 percent of the amount of opioid required to produce the same, similar, or better analgesic effect with the opioid alone.
  • the amount of opioid present in the pharmaceutical combination is less than about 200 mg, less than about 190 mg, less than about 180 mg, less than about 170 mg, less than about 160 mg, less than about 150 mg, less than about 140 mg, less than about 130 mg, less than about 120 mg, less than about 100 mg, less than about 90 mg, less than about 80 mg, less than about 75 mg, less than about 70 mg, less than about 65 mg, less than about 60 mg, less than about 55 mg, less than about 50 mg, less than about 45 mg, less than about 40 mg, less than about 35 mg, less than about 30 mg, less than about 25 mg, less than about 20 mg, less than about 15 mg, less than about 12 mg, less than about 10 mg, less than about 9 mg, less than about 8 mg, less than about 7.5 mg, less than about 7 mg, less than about 6 mg, less than about 5 mg, less than about 4 mg, less than about 3 mg, less than about 2.5 mg, less than about 2 mg, less than about 1.5 mg, less than about 1 mg
  • the opioid is buprenorphine and buprenorphine is present in the pharmaceutical combination in an amount that is at least about 20 percent less, at least about 25 percent less, at least about 30 percent less, at least about 40 percent less, at least 2 times less, at least 5 times less, or at least 7 times less than the amount of buprenorphine required to produce the same, similar, or better analgesic effect with buprenorphine alone.
  • buprenorphine is present in the pharmaceutical combination in an amount that is at least 7 times less than the amount of buprenorphine required to produce the same, similar, or better effect with buprenorphine alone.
  • the opioid is buprenorphine and buprenorphine is present in the pharmaceutical combination in an amount that is at least about 20 percent less, at least about 25 percent less, at least about 30 percent less, at least about 40 percent less, at least 2 times less, at least 5 times less, or at least 7 times less than the amount of buprenorphine required to produce the same, similar,
  • buprenorphine is present in the pharmaceutical combination in an amount that is about 2 percent, about 3 percent, about 4 percent, about 5 percent, about 6 percent, about 7 percent, about 8 percent, about 9 percent, about 10 percent, about 12 percent, or about 15 percent of the amount of buprenorphine required to produce the same, similar, or better analgesic effect with buprenorphine alone. In certain embodiments, buprenorphine is present in the pharmaceutical combination in an amount that is about 12 percent, or about 15 percent of the amount of buprenorphine required to produce the same, similar, or better analgesic effect with buprenorphine alone. In other embodiments, buprenorphine is present in the
  • the opioid is buprenorphine and the amount of
  • buprenorphine present in the pharmaceutical combination is less than about 200 mg, less than about 190 mg, less than about 180 mg, less than about 170 mg, less than about 160 mg, less than about 150 mg, less than about 140 mg, less than about 130 mg, less than about 120 mg, less than about 100 mg, less than about 90 mg, less than about 80 mg, less than about 75 mg, less than about 70 mg, less than about 65 mg, less than about 60 mg, less than about 55 mg, less than about 50 mg, less than about 45 mg, less than about 40 mg, less than about 35 mg, less than about 30 mg, less than about 25 mg, less than about 20 mg, less than about 15 mg, less than about 12 mg, less than about 10 mg, less than about 9 mg, less than about 8 mg, less than about 7.5 mg, less than about 7 mg, less than about 6 mg, less than about 5 mg, less than about 4 mg, less than about 3 mg, less than about 2.5 mg, less than about 2 mg, less than about 1.5 mg, less than about 1 mg, less than about 0.9
  • the amount of buprenorphine present in the pharmaceutical combination is less than about 12 mg, less than about 10 mg, less than about 8 mg, less than about 6 mg, less than about 4 mg, less than about 2 mg, less than about 1 mg, less than about 0.9 mg, less than about 0.8 mg, less than about 0.75 mg, less than about 0.6 mg, less than about 0.5 mg, less than about 0.4 mg, less than about 0.3 mg, less than about 0.2 mg, less than about 0.1 mg, less than about 0.075 mg, less than about 0.050 mg, less than about 0.020 mg, less than about 0.010 mg, or less than about 0.005 mg.
  • the opioid is hydrocodone and hydrocodone is present in the pharmaceutical combination in an amount that is at least about 20 percent less, at least about 25 percent less, at least about 30 percent less, at least about 40 percent less, at least 2 times less, at least 5 times less, at least 7 times less, at least 10 times less or at least 12 times less than the amount of hydrocodone required to produce the same, similar, or better effect with hydrocodone alone.
  • hydrocodone is present in the
  • hydrocodone is present in the pharmaceutical combination in an amount that is at least 12 times less than the amount of hydrocodone required to produce the same, similar, or better effect with hydrocodone alone.
  • hydrocodone is present in the pharmaceutical combination in an amount that is about 2 percent, about 3 percent, about 4 percent, about 5 percent, about 6 percent, about 7 percent, or about 8 percent of the amount of hydrocodone required to produce the same, similar, or better analgesic effect with hydrocodone alone.
  • hydrocodone is present in the pharmaceutical combination in an amount that is about 8 percent of the amount of hydrocodone required to produce the same, similar, or better analgesic effect with hydrocodone alone.
  • hydrocodone is present in the pharmaceutical combination in an amount that is between about 7 percent and about 10 percent of the amount of hydrocodone required to produce the same, similar, or better analgesic effect with hydrocodone alone.
  • the opioid is hydrocodone and the amount of hydrocodone present in the pharmaceutical combination is less than about 200 mg, less than about 190 mg, less than about 180 mg, less than about 170 mg, less than about 160 mg, less than about 150 mg, less than about 140 mg, less than about 130 mg, less than about 120 mg, less than about 100 mg, less than about 90 mg, less than about 80 mg, less than about 75 mg, less than about 70 mg, less than about 65 mg, less than about 60 mg, less than about 55 mg, less than about
  • the amount of hydrocodone present in the pharmaceutical combination is less than about 120 mg, less than about 100 mg, less than about 90 mg, less than about 80 mg, less than about 70 mg, less than about 60 mg, less than about 50 mg, less than about 40 mg, less than about 30 mg, less than about 20 mg, less than about 15 mg, less than about 10 mg, less than about 5 mg, less than about 2.5 mg, or less than about 1 mg.
  • the opioid is codeine and codeine is present in the pharmaceutical combination in an amount that is at least about 20 percent less, at least about 25 percent less, at least about 30 percent less, at least about 40 percent less, at least 2 times less, at least 5 times less, at least 7 times less, at least 10 times less, at least 12 times less, at least 15 times less, at least 17 times less, at least 20 times less or at least 25 times less than the amount of codeine required to produce the same, similar, or better analgesic effect with codeine alone.
  • codeine is present in the pharmaceutical combination in an amount that is at least 25 times less than the amount of codeine required to produce the same, similar, or better analgesic effect with codeine alone.
  • codeine is present in the pharmaceutical combination in an amount that is about 2 percent, about 3 percent, or about 4 percent of the amount of codeine required to produce the same, similar, or better analgesic effect with codeine alone. In certain embodiments, codeine is present in the pharmaceutical combination in an amount that is about 4 percent of the amount of codeine required to produce the same, similar, or better analgesic effect with codeine alone. In other embodiments, codeine is present in the pharmaceutical combination in an amount that is between about 2 percent and about 5 percent of the amount of codeine required to produce the same, similar, or better analgesic effect with codeine alone.
  • the opioid is codeine and the amount of codeine present in the pharmaceutical combination is less than about 200 mg, less than about 190 mg, less than about 180 mg, less than about 170 mg, less than about 160 mg, less than about 150 mg, less than about 140 mg, less than about 130 mg, less than about 120 mg, less than about 100 mg, less than about 90 mg, less than about 80 mg, less than about 75 mg, less than about 70 mg, less than about 65 mg, less than about 60 mg, less than about 55 mg, less than about 50 mg, less than about 45 mg, less than about 40 mg, less than about 35 mg, less than about 30 mg, less than about 25 mg, less than about 20 mg, less than about 15 mg, less than about 12 mg, less than about 10 mg, less than about 9 mg, less than about 8 mg, less than about 7.5 mg, less than about 7 mg, less than about 6 mg, less than about 5 mg, less than about 4 mg, less than about 3 mg, less than about 2.5 mg, less than about 2 mg, less than about 1.5
  • the opioid is morphine and morphine is present in the pharmaceutical combination in an amount that is at least about 20 percent less, at least about 25 percent less, at least about 30 percent less, at least about 40 percent less, at least 2 times less than the amount of morphine required to produce the same, similar, or better analgesic effect with morphine alone.
  • morphine is present in the pharmaceutical combination in an amount that is about 10 percent, about 15 percent, about 20 percent, about 25 percent, about 30 percent, about 35 percent, about 40 percent, about 45 percent or about 50 percent of the amount of morphine required to produce the same, similar, or better analgesic effect with morphine alone.
  • morphine is present in the pharmaceutical combination in an amount that is about 45 percent or about 50 percent of the amount of morphine required to produce the same, similar, or better analgesic effect with morphine alone. In other embodiments, morphine is present in the pharmaceutical combination in an amount that is between about 45 percent and about 50 percent of the amount of morphine required to produce the same, similar, or better analgesic effect with morphine alone.
  • the opioid is morphine and the amount of morphine present in the pharmaceutical combination is less than about 200 mg, less than about 190 mg, less than about 180 mg, less than about 170 mg, less than about 160 mg, less than about 150 mg, less than about 140 mg, less than about 130 mg, less than about 120 mg, less than about 100 mg, less than about 90 mg, less than about 80 mg, less than about 75 mg, less than about 70 mg, less than about 65 mg, less than about 60 mg, less than about 55 mg, less than about 50 mg, less than about 45 mg, less than about 40 mg, less than about 35 mg, less than about 30 mg, less than about 25 mg, less than about 20 mg, less than about 15 mg, less than about 12 mg, less than about 10 mg, less than about 9 mg, less than about 8 mg, less than about 7.5 mg, less than about 7 mg, less than about 6 mg, less than about 5 mg, less than about 4 mg, less than about 3 mg, less than about 2.5 mg, less than about 2 mg, less than about
  • the amount of morphine present in the pharmaceutical combination is less than about 200 mg, less than about 150 mg, less than about 130 mg, less than about 120 mg, less than about 100 mg, less than about 90 mg, less than about 80 mg, less than about 75 mg, less than about 70 mg, less than about 60 mg, less than about 50 mg, less than about 45 mg, less than about 40 mg, less than about 30 mg, less than about 25 mg, less than about 20 mg, less than about 15 mg, less than about 12 mg, less than about 10 mg, less than about 8 mg, less than about 7.5 mg, less than about 5 mg, less than about 4 mg, less than about 2.5 mg, less than about 2 mg, less than about 1 mg, less than about 0.7 mg, or less than about 0.5 mg.
  • the opioid is oxycodone and oxycodone is present in the pharmaceutical combination in an amount that is at least about 20 percent less, at least about 25 percent less, at least about 30 percent less, at least about 40 percent less, at least 2 times less, at least 5 times less, at least 7 times less, at least 10 times less, at least 12 times less, at least 15 times less, at least 17 times less, at least 20 times less or at least 25 times less than the amount of oxycodone required to produce the same, similar, or better analgesic effect with the oxycodone alone.
  • the amount of oxycodone is at least about 20 percent less, at least about 25 percent less, at least about 30 percent less, at least about 40 percent less, at least 2 times less, at least 7 times less, at least 12 times less, at least 17 times less, or at least 25 times less than the amount of oxycodone required to produce the same, similar, or better analgesic effect with the oxycodone alone.
  • the amount of oxycodone is between about 20 percent and about 25 percent less, between about 25 percent and about 30 percent less, between about 30 percent and about 40 percent less, between about 40 percent and about 50 percent less, between about 2 times and about 5 times less, between about 5 times and about 10 times less, between about 10 times and about 15 times less, between about 15 times and about 20 times less, or between about 20 times and about 25 times less than the amount of oxycodone required to produce the same, similar, or better analgesic effect with the oxycodone alone.
  • the opioid is oxycodone and the amount of oxycodone present in the pharmaceutical combination is less than about 200 mg, less than about 190 mg, less than about 180 mg, less than about 170 mg, less than about 160 mg, less than about 150 mg, less than about 140 mg, less than about 130 mg, less than about 120 mg, less than about 100 mg, less than about 90 mg, less than about 80 mg, less than about 75 mg, less than about 70 mg, less than about 65 mg, less than about 60 mg, less than about 55 mg, less than about
  • the amount of oxycodone present in the pharmaceutical combination is less than about 100 mg, less than about 80 mg, less than about 60 mg, less than about 40 mg, less than about 30 mg, less than about 20 mg, less than about 15 mg, less than about 10 mg, or less than about 5 mg.
  • the opioid is methadone and methadone is present in the pharmaceutical combination in an amount that is at least about 20 percent less, at least about 25 percent less, at least about 30 percent less, at least about 40 percent less, at least 2 times less, at least 5 times less, at least 7 times less, at least 10 times less, at least 12 times less, at least 15 times less, at least 17 times less, at least 20 times less or at least 25 times less than the amount of methadone required to produce the same, similar, or better analgesic effect with the methadone alone.
  • the amount of methadone is at least about 20 percent less, at least about 25 percent less, at least about 30 percent less, at least about 40 percent less, at least 2 times less, at least 7 times less, at least 12 times less, at least 17 times less, or at least 25 times less than the amount of methadone required to produce the same, similar, or better analgesic effect with the methadone alone.
  • the amount of methadone is between about 20 percent and about 25 percent less, between about 25 percent and about 30 percent less, between about 30 percent and about 40 percent less, between about 40 percent and about 50 percent less, between about 2 times and about 5 times less, between about 5 times and about 10 times less, between about 10 times and about 15 times less, between about 15 times and about 20 times less, or between about 20 times and about 25 times less than the amount of methadone required to produce the same, similar, or better analgesic effect with the methadone alone.
  • the opioid is methadone and the amount of methadone present in the pharmaceutical combination is less than about 200 mg, less than about 190 mg, less than about 180 mg, less than about 170 mg, less than about 160 mg, less than about 150 mg, less than about 140 mg, less than about 130 mg, less than about 120 mg, less than about 100 mg, less than about 90 mg, less than about 80 mg, less than about 75 mg, less than about 70 mg, less than about 65 mg, less than about 60 mg, less than about 55 mg, less than about
  • the amount of methadone in the pharmaceutical combination is less than about 40 mg, less than about 30 mg, less than about 20 mg, less than about 15 mg, less than about 10 mg, less than about 7.5 mg, less than about 5 mg, or less than about 2.5 mg.
  • the opioid is hydromorphone and hydromorphone is present in the pharmaceutical combination in an amount that is at least about 20 percent less, at least about 25 percent less, at least about 30 percent less, at least about 40 percent less, at least 2 times less, at least 5 times less, at least 7 times less, at least 10 times less, at least 12 times less, at least 15 times less, at least 17 times less, at least 20 times less or at least 25 times less than the amount of hydromorphone required to produce the same, similar, or better analgesic effect with the hydromorphone alone.
  • the opioid is hydromorphone and hydromorphone is present in the pharmaceutical combination in an amount that is at least about 20 percent less, at least about 25 percent less, at least about 30 percent less, at least about 40 percent less, at least 2 times less, at least 5 times less, at least 7 times less, at least 10 times less, at least 12 times less, at least 15 times less, at least 17 times less, at least 20 times less or at least 25 times less than the amount of hydromorphone required to produce the same, similar, or better anal
  • the amount of hydromorphone is at least about 20 percent less, at least about 25 percent less, at least about 30 percent less, at least about 40 percent less, at least 2 times less, at least 7 times less, at least 12 times less, at least 17 times less, or at least 25 times less than the amount of hydromorphone required to produce the same, similar, or better analgesic effect with the hydromorphone alone.
  • the amount of hydromorphone is between about 20 percent and about 25 percent less, between about 25 percent and about 30 percent less, between about 30 percent and about 40 percent less, between about 40 percent and about 50 percent less, between about 2 times and about 5 times less, between about 5 times and about 10 times less, between about 10 times and about 15 times less, between about 15 times and about 20 times less, or between about 20 times and about 25 times less than the amount of hydromorphone required to produce the same, similar, or better analgesic effect with the hydromorphone alone.
  • the opioid is hydromorphone and the amount of hydromorphone present in the pharmaceutical combination is less than about 200 mg, less than about 190 mg, less than about 180 mg, less than about 170 mg, less than about 160 mg, less than about 150 mg, less than about 140 mg, less than about 130 mg, less than about 120 mg, less than about 100 mg, less than about 90 mg, less than about 80 mg, less than about 75 mg, less than about 70 mg, less than about 65 mg, less than about 60 mg, less than about 55 mg, less than about 50 mg, less than about 45 mg, less than about 40 mg, less than about 35 mg, less than about 30 mg, less than about 25 mg, less than about 20 mg, less than about 15 mg, less than about 12 mg, less than about 10 mg, less than about 9 mg, less than about 8 mg, less than about 7.5 mg, less than about 7 mg, less than about 6 mg, less than about 5 mg, less than about 4 mg, less than about 3 mg, less than about 2.5 mg, less than about 2 mg, less than about
  • the amount of hydromorphone in the pharmaceutical combination is less than about 40 mg, less than about 30 mg, less than about 20 mg, less than about 15 mg, less than about 10 mg, less than about 7.5 mg, less than about 5 mg, or less than about 2 mg.
  • the opioid is oxymorphone and oxymorphone is present in the pharmaceutical combination in an amount that is at least about 20 percent less, at least about 25 percent less, at least about 30 percent less, at least about 40 percent less, at least 2 times less, at least 5 times less, at least 7 times less, at least 10 times less, at least 12 times less, at least 15 times less, at least 17 times less, at least 20 times less or at least 25 times less than the amount of oxymorphone required to produce the same, similar, or better analgesic effect with the oxymorphone alone.
  • the amount of oxymorphone is at least about 20 percent less, at least about 25 percent less, at least about 30 percent less, at least about 40 percent less, at least 2 times less, at least 7 times less, at least 12 times less, at least 17 times less, or at least 25 times less than the amount of oxymorphone required to produce the same, similar, or better analgesic effect with the oxymorphone alone.
  • the amount of oxymorphone is between about 20 percent and about 25 percent less, between about 25 percent and about 30 percent less, between about 30 percent and about 40 percent less, between about 40 percent and about 50 percent less, between about 2 times and about 5 times less, between about 5 times and about 10 times less, between about 10 times and about 15 times less, between about 15 times and about 20 times less, or between about 20 times and about 25 times less than the amount of oxymorphone required to produce the same, similar, or better analgesic effect with the oxymorphone alone.
  • the opioid is oxymorphone and the amount of
  • oxymorphone present in the pharmaceutical combination is less than about 200 mg, less than about 190 mg, less than about 180 mg, less than about 170 mg, less than about 160 mg, less than about 150 mg, less than about 140 mg, less than about 130 mg, less than about 120 mg, less than about 100 mg, less than about 90 mg, less than about 80 mg, less than about 75 mg, less than about 70 mg, less than about 65 mg, less than about 60 mg, less than about 55 mg, less than about 50 mg, less than about 45 mg, less than about 40 mg, less than about 35 mg, less than about 30 mg, less than about 25 mg, less than about 20 mg, less than about 15 mg, less than about 12 mg, less than about 10 mg, less than about 9 mg, less than about 8 mg, less than about 7.5 mg, less than about 7 mg, less than about 6 mg, or less than about 5 mg.
  • the amount of oxymorphone in the pharmaceutical combination is less than about 40 mg, less than about 30 mg, less than about 20 mg, less than about 15 mg, less than about 10 mg, less than about 7.5 mg, or less than about 5 mg.
  • the opioid is tramadol and tramadol is present in the pharmaceutical combination in an amount that is at least about 20 percent less, at least about 25 percent less, at least about 30 percent less, at least about 40 percent less, at least 2 times less, at least 5 times less, at least 7 times less, at least 10 times less, at least 12 times less, at least 15 times less, at least 17 times less, at least 20 times less or at least 25 times less than the amount of tramadol required to produce the same, similar, or better analgesic effect with the tramadol alone.
  • the amount of tramadol is at least about 20 percent less, at least about 25 percent less, at least about 30 percent less, at least about 40 percent less, at least 2 times less, at least 7 times less, at least 12 times less, at least 17 times less, or at least 25 times less than the amount of tramadol required to produce the same, similar, or better analgesic effect with the tramadol alone.
  • the amount of tramadol is between about 20 percent and about 25 percent less, between about 25 percent and about 30 percent less, between about 30 percent and about 40 percent less, between about 40 percent and about 50 percent less, between about 2 times and about 5 times less, between about 5 times and about 10 times less, between about 10 times and about 15 times less, between about 15 times and about 20 times less, or between about 20 times and about 25 times less than the amount of tramadol required to produce the same, similar, or better analgesic effect with the tramadol alone.
  • the opioid is tramadol and the amount of tramadol present in the pharmaceutical combination is less than about 200 mg, less than about 190 mg, less than about 180 mg, less than about 170 mg, less than about 160 mg, less than about 150 mg, less than about 140 mg, less than about 130 mg, less than about 120 mg, less than about 100 mg, less than about 90 mg, less than about 80 mg, less than about 75 mg, less than about 70 mg, less than about 65 mg, less than about 60 mg, less than about 55 mg, less than about 50 mg, less than about 45 mg, less than about 40 mg, less than about 35 mg, less than about 30 mg, less than about 25 mg, or less than about 20 mg,.
  • the opioid is methadone
  • the amount of methadone in the pharmaceutical combination is less than about 40 mg, less than about 30 mg, or less than about 20 mg.
  • the pharmaceutical combination comprises the cannabinoid and the opioid in amounts such that the amount of cannabinoid is at least 20 percent less than required to produce the same, similar or better analgesic effect with the cannabinoid alone.
  • the pharmaceutical combination is a therapeutically effective amount.
  • the amount of the cannabinoid present in the pharmaceutical combination is a sub -therapeutic amount.
  • the present disclosure provides a co-administered pharmaceutical combination or a fixed-dose pharmaceutical combination comprising a cannabinoid and an opioid that is prepared in a variety of formulations or dosage forms.
  • the pharmaceutical combination is prepared in a form suitable for enteral/gastrointestinal or parenteral administration.
  • the pharmaceutical combination is prepared in a form suitable for oral, transmucosal, nasal, intrapulmonary, rectal, transdermal, intradermal, intravenous, intramuscular, or subcutaneous administration.
  • the pharmaceutical combination is a fixed-dose pharmaceutical combination.
  • the cannabinoid and opioid are prepared in a single dosage form.
  • the pharmaceutical combination is prepared in a form suitable for oral administration.
  • the pharmaceutical combination is prepared in a form suitable for buccal or sublingual administration.
  • the form suitable for oral administration is a solution, a suspension, an emulsion, an elixir, a syrup, a paste, a tablet, a capsule, a powder, a granule, a concentrate, a film, a lozenge/troche, drops, a spray, or a swab.
  • the form suitable for oral administration is a tablet, a pill, a capsule, a sublingual, a solution, or a syrup.
  • the pharmaceutical combination is prepared in a form suitable for nasal administration.
  • the form suitable for nasal administration is an aerosol, a spray, or an inhalant.
  • the pharmaceutical combination is prepared in a form suitable for rectal administration.
  • the form suitable for rectal administration is a suppository.
  • the pharmaceutical combination is prepared in a form suitable for parenteral administration.
  • parenteral administration includes, but is not limited to, intravenous, intramuscular, intradermal and subcutaneous administration.
  • the form suitable for parenteral administration is a solution, a suspension, a powder, or an implant.
  • the pharmaceutical combination is prepared in a form suitable for epidural administration.
  • the pharmaceutical combination is prepared in a form suitable for intravenous administration.
  • the pharmaceutical combination is prepared in solution form suitable for administration by injection, by pump infusion, or by drip infusion.
  • the pharmaceutical combination is in a form suitable for transdermal administration.
  • the form suitable for transdermal administration is a patch, a cream, a film, a gel, a jelly, a lotion, an ointment, a concentrate, a suspension, an emulsion, a paste, an oil, or a tincture.
  • the form suitable for transdermal administration is transdermal patch.
  • the pharmaceutical combination is a co-administered pharmaceutical combination. In certain embodiments wherein the pharmaceutical
  • the cannabinoid and opioid are provided in two separate dosage forms, wherein the two dosage forms may be the same or different.
  • the individual dosage forms for the cannabinoid and the opioid may be suitable for separate routes and modes of administration.
  • the cannabinoid is independently prepared in a form suitable for oral, nasal, rectal, parenteral or transdermal administration and the opioid is independently prepared in a form suitable for oral, nasal, rectal, parenteral or transdermal administration.
  • the cannabinoid and opioid are prepared in forms suitable for oral administration.
  • the cannabinoid and opioid are prepared in forms suitable for nasal administration.
  • the cannabinoid and opioid are prepared in forms suitable for rectal administration.
  • the cannabinoid and opioid are prepared in forms suitable for parenteral administration.
  • the cannabinoid and opioid are prepared in forms suitable for transdermal administration.
  • the cannabinoid is prepared in a form suitable for oral administration and the opioid is prepared in a form suitable for nasal administration.
  • the cannabinoid is prepared in a form suitable for oral administration and the opioid is prepared in a form suitable for rectal administration.
  • the cannabinoid is prepared in a form suitable for oral administration and the opioid is prepared in a form suitable for parenteral administration.
  • the cannabinoid is prepared in a form suitable for oral administration and the opioid is prepared in a form suitable for transdermal administration.
  • the cannabinoid is prepared in a form suitable for nasal administration and the opioid is prepared in a form suitable for oral administration.
  • the cannabinoid is prepared in a form suitable for nasal administration and the opioid is prepared in a form suitable for rectal administration.
  • the cannabinoid is prepared in a form suitable for nasal administration and the opioid is prepared in a form suitable for parenteral administration.
  • the cannabinoid is prepared in a form suitable for nasal administration and the opioid is prepared in a form suitable for transdermal administration.
  • the cannabinoid is prepared in a form suitable for rectal administration and the opioid is prepared in a form suitable for oral administration.
  • the cannabinoid is prepared in a form suitable for rectal administration and the opioid is prepared in a form suitable for nasal administration.
  • the cannabinoid is prepared in a form suitable for rectal administration and the opioid is prepared in a form suitable for parenteral administration. In yet other embodiments, the cannabinoid is prepared in a form suitable for rectal administration and the opioid is prepared in a form suitable for transdermal
  • the cannabinoid is prepared in a form suitable for parenteral administration and the opioid is prepared in a form suitable for oral administration.
  • the cannabinoid is prepared in a form suitable for parenteral administration and the opioid is prepared in a form suitable for nasal administration.
  • the cannabinoid is prepared in a form suitable for parenteral administration and the opioid is prepared in a form suitable for rectal administration.
  • the cannabinoid is prepared in a form suitable for parenteral administration and the opioid is prepared in a form suitable for transdermal administration.
  • the cannabinoid is prepared in a form suitable for transdermal administration and the opioid is prepared in a form suitable for oral administration. In some embodiments, the cannabinoid is prepared in a form suitable for transdermal administration and the opioid is prepared in a form suitable for nasal administration. In other embodiments, the cannabinoid is prepared in a form suitable for transdermal administration and the opioid is prepared in a form suitable for rectal administration. In yet other embodiments, the cannabinoid is prepared in a form suitable for transdermal administration and the opioid is prepared in a form suitable for parenteral administration.
  • the cannabinoid is prepared in a form suitable for oral administration.
  • the cannabinoid is prepared in a form suitable for buccal or sublingual administration.
  • the form of the cannabinoid suitable for oral administration is a solution, a suspension, an emulsion, an elixir, a syrup, a paste, a tablet, a capsule, a powder, a granule, a concentrate, a film, a lozenge/troche, drops, a spray, or a swab.
  • the form of the cannabinoid suitable for oral administration is a tablet, a pill, a capsule, a sublingual, a solution, or a syrup.
  • the opioid is prepared in a form suitable for oral administration.
  • the opioid is prepared in a form suitable for buccal or sublingual
  • the form of the opioid suitable for oral administration is a solution, a suspension, an emulsion, an elixir, a syrup, a paste, a tablet, a capsule, a powder, a granule, a concentrate, a film, a lozenge/troche, drops, a spray, or a swab.
  • the form of the opioid suitable for oral administration is a tablet, a pill, a capsule, a sublingual, a solution, or a syrup.
  • the cannabinoid is prepared in a form suitable for nasal administration.
  • the form of the cannabinoid suitable for nasal administration is an aerosol, a spray, or an inhalant.
  • the opioid is prepared in a form suitable for nasal administration.
  • the form of the opioid suitable for nasal administration is an aerosol, a spray, or an inhalant.
  • the cannabinoid is prepared in a form suitable for rectal administration.
  • the form of the cannabinoid suitable for rectal administration is a suppository.
  • the opioid is prepared in a form suitable for rectal administration.
  • the form of the opioid suitable for rectal administration is a suppository.
  • the cannabinoid is prepared in a form suitable for parenteral administration.
  • the cannabinoid is prepared in a form suitable for intravenous, intramuscular, intradermal and subcutaneous administration.
  • the form of the cannabinoid suitable for parenteral administration is a solution, a suspension, a powder, or an implant.
  • the cannabinoid is prepared in a form suitable for epidural administration.
  • the cannabinoid is prepared in a form suitable for intravenous administration.
  • the cannabinoid is prepared in solution form suitable for administration by injection, by pump infusion, or by drip infusion.
  • the opioid is prepared in a form suitable for parenteral administration.
  • the opioid is prepared in a form suitable for intravenous, intramuscular, intradermal and subcutaneous administration.
  • the form of the opioid suitable for parenteral administration is a solution, a suspension, a powder, or an implant.
  • the opioid is prepared in a form suitable for epidural administration.
  • the opioid is prepared in a form suitable for intravenous administration.
  • the opioid is prepared in solution form suitable for administration by injection, by pump infusion, or by drip infusion.
  • the cannabinoid is in a form suitable for transdermal administration.
  • the form of the cannabinoid suitable for transdermal administration is a patch, a cream, a film, a gel, a jelly, a lotion, an ointment, a concentrate, a suspension, an emulsion, a paste, an oil, or a tincture.
  • the form of the cannabinoid suitable for transdermal administration is transdermal patch.
  • the opioid is in a form suitable for transdermal
  • the form of the opioid suitable for transdermal administration is a patch, a cream, a film, a gel, a jelly, a lotion, an ointment, a concentrate, a suspension, an emulsion, a paste, an oil, or a tincture.
  • the form of the opioid suitable for transdermal administration is transdermal patch.
  • the present disclosure provides for modulation of onset of action and duration of action to promote either cannabinoid or opioid onset of action, and modulate the duration of action for either the cannabinoid or the opioid, or both, in order to produce the most synergistically beneficial outcome given the needs of the particular patient.
  • the present disclosure provides for modulation of onset of action and duration of action in either the cannabinoid or the opioid, or both, in all routes of administration, including the routes of administration disclosed herein.
  • the onset action of cannabinoid may occur first, and the onset of action of the opioid release is delayed to support a better synergistic efficacy of the pharmaceutical combination.
  • the duration of dronabinol may be adjusted to complement the desired action effect synergistically with the opioid or opioids, and in a synergistically complementary manner, the onset of the opioid, individually, or the onset of the opioids in combination or each independently, may be adjusted so that the individual or combination onset of actions occurs to provide the desired synergistic effect with the dronabinol.
  • the pharmaceutical combination is prepared in a form suitable for immediate release, delayed release, extended release.
  • the pharmaceutical combination comprises a cannabinoid, wherein the cannabinoid is prepared in a form suitable for immediate release, delayed release, or extended release.
  • the pharmaceutical combination comprises an opioid, wherein the opioid is prepared in a form suitable for immediate release, delayed release, or extended release.
  • the pharmaceutical combination can be prepared in a form wherein the cannabinoid and opioid exhibit the same or different release profiles.
  • the pharmaceutical combination comprises a cannabinoid and an opioid, wherein the cannabinoid and the opioid are independently prepared in a form suitable for immediate release, delayed release, or extended release.
  • the cannabinoid and the opioid are prepared in a form suitable for immediate release.
  • the cannabinoid and the opioid are prepared in a form suitable for delayed release.
  • the cannabinoid and the opioid are prepared in a form suitable for extended release.
  • the cannabinoid is prepared in a form suitable for immediate release, and the opioid is prepared in a form suitable for delayed release. In yet other embodiments, the cannabinoid is prepared in a form suitable for immediate release, and the opioid is prepared in a form suitable for extended release. In still yet other embodiments, the cannabinoid is prepared in a form suitable for immediate release, and the opioid is prepared in a form suitable for extended release. In some embodiments, the cannabinoid is prepared in a form suitable for delayed release, and the opioid is prepared in a form suitable for immediate release. In certain embodiments, the cannabinoid is prepared in a form suitable for delayed release, and the opioid is prepared in a form suitable for extended release.
  • the cannabinoid is prepared in a form suitable for extended release, and the opioid is prepared in a form suitable for immediate release. In yet another embodiment, the cannabinoid is prepared in a form suitable for extended release and the opioid is prepared in a form suitable for delayed release.
  • the opioid is buprenorphine and the pharmaceutical combination is prepared in a form suitable for oral administration.
  • the form suitable for oral administration is a tablet, a pill, a capsule or a sublingual.
  • the opioid is buprenorphine
  • the form suitable for buccal administration is a buccal film.
  • the opioid is buprenorphine
  • the form suitable for transdermal administration is a transdermal patch.
  • the pharmaceutical combination comprises long-chain fatty acids to provide increased absorption.
  • the opioid is hydrocodone and the pharmaceutical combination is in a form suitable for oral administration.
  • the form suitable for oral administration is a tablet, a pill, a capsule or a sublingual.
  • the opioid is codeine and the pharmaceutical combination is in a form suitable for oral administration.
  • the form suitable for oral administration is a tablet, a pill, a capsule or a syrup.
  • the opioid is morphine and the pharmaceutical
  • the combination is in a form suitable for oral administration.
  • the opioid is morphine
  • the form suitable for oral administration is a tablet, a pill, or a capsule.
  • the opioid is oxycodone and the pharmaceutical combination is in a form suitable for oral administration.
  • the form suitable for oral administration is a tablet, a capsule, or a solution.
  • the opioid is methadone and the pharmaceutical combination is in a form suitable for oral administration.
  • the form suitable for oral administration is a tablet, a capsule, a solution, a concentrate, a syrup, or a powder.
  • the opioid is methadone and the pharmaceutical combination is in a form suitable for intravenous injection.
  • the opioid is hydromorphone and the pharmaceutical combination is in a form suitable for oral administration.
  • the form suitable for oral administration is a tablet, a capsule, a solution, a concentrate, a syrup, or a powder.
  • the opioid is
  • hydromorphone and the pharmaceutical combination is in a form suitable for intravenous injection.
  • the opioid is oxymorphone and the pharmaceutical combination is in a form suitable for oral administration.
  • the form suitable for oral administration is a tablet, a capsule, a solution, a concentrate, a syrup, or a powder.
  • the opioid is
  • the opioid is oxymorphone and the pharmaceutical combination is in a form suitable for intravenous injection.
  • the opioid is oxymorphone and the pharmaceutical combination is in a form suitable for rectal administration.
  • the opioid is tramadol and the pharmaceutical combination is in a form suitable for oral administration.
  • the form suitable for oral administration is a tablet, a capsule, a solution, a concentrate, a syrup, or a powder.
  • the cannabinoid and the opioid may be prepared in the same form, as with a fixed- dose combination or a co-administered combination, or in different forms, as with a co administered combination.
  • the present disclosure provides for a pharmaceutical
  • the pharmaceutical combination comprises a cannabinoid and an opioid, and one or more pharmaceutically acceptable carriers, excipients, diluents, and/or adjuvants, or any combination thereof.
  • the present disclosure provides for a pharmaceutical composition, wherein the composition comprises a pharmaceutical combination comprising a cannabinoid and an opioid, and one or more pharmaceutically binders, stabilizers, buffering agents, emulsifiers, osmotic agents, coatings, colorings, or flavorings, or any combination thereof.
  • the pharmaceutical combination further comprises a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier provides increased absorption of the pharmaceutical combination.
  • the pharmaceutically acceptable carrier is selected from the group consisting of: long-chain fatty acids, and sesame oil, and a combination thereof.
  • the pharmaceutically acceptable carrier is long-chain fatty acids.
  • the pharmaceutically acceptable carrier is sesame oil.
  • the pharmaceutically acceptable carrier is sesame oil.
  • pharmaceutically acceptable carrier is a combination of long-chain fatty acids and sesame oil.
  • the present disclosure also provides for a method for pain management, comprising administering a pharmaceutical combination comprising a cannabinoid and an opioid.
  • the pharmaceutical combination is a co-administered combination or a fixed-dose combination.
  • the method of treating or preventing pain comprises administering a pharmaceutical combination comprising dronabinol and an opioid.
  • the method of treating or preventing pain comprises administering a pharmaceutical combination comprising dronabinol and two or more opioids for a blended pharmacodynamic profile.
  • the pharmaceutical combination comprising a cannabinoid and an opioid.
  • the pharmaceutical combination is a co-administered combination or a fixed-dose combination.
  • the method of treating or preventing pain comprises administering a pharmaceutical combination comprising dronabinol and an opioid.
  • the method of treating or preventing pain comprises administering a pharmaceutical combination comprising dronabinol and two or more opioids for a blended pharmacodynamic profile.
  • the pharmaceutical combination comprising a cannabinoid
  • the pharmaceutical combination comprises dronabinol and an opioid selected from the group consisting of buprenorphine, hydrocodone, codeine, morphine, methadone, oxymorphone, hydromorphone, tramadol, and oxycodone, and any combination thereof.
  • the pharmaceutical combination comprises dronabinol and an opioid selected from the group consisting of buprenorphine, hydrocodone, codeine, morphine, methadone, oxymorphone, hydromorphone, tramadol, and oxycodone.
  • the pharmaceutical combination comprises dronabinol and buprenorphine.
  • the pharmaceutical combination is synergistically effective.
  • the preferred route of administration may depend upon the condition being treated, the combination of cannabinoid and opioid being administered, and the medical history and condition of the subject being treated.
  • a fixed-dose combination of a cannabinoid and an opioid in a single dosage form may be administered via the same route and mode.
  • the route of administration is pharmaceutical combination is
  • the pharmaceutical combination is administered transmucosally, intranasally, intrapulmonary, rectally, transdermally, intradermally, intravenously, intramuscularly, intraurethrally, intravaginally, intrauterally, or
  • a co-administered combination of a cannabinoid and opioid may be administered via the same or different route, and further, if via the same route, by the same or different dosage form.
  • the pharmaceutical combination is a co- administered combination wherein the cannabinoid and the opioid are each independently administered orally, transmucosally, intranasally, intrapulmonary, rectally, transdermally, intradermally, intravenously, intramuscularly, intraurethrally, intravaginally, intrauterally, or subcutaneously.
  • the pharmaceutical combination is administered orally. In other embodiments, the pharmaceutical combination is administered transdermally. In yet other embodiments, the pharmaceutical combination is administered intravenously.
  • the cannabinoid is dronabinol and the pharmaceutical combination is administered orally.
  • the pharmaceutical combination is administered as a capsule or a solution.
  • the cannabinoid is dronabinol
  • the dronabinol is administered orally.
  • the cannabinoid is dronabinol
  • the dronabinol is administered as a capsule or a solution.
  • the opioid is buprenorphine and the pharmaceutical combination is administered orally. In certain embodiments wherein the opioid is
  • the pharmaceutical combination is administered as a tablet, a pill, a capsule or a sublingual.
  • the opioid is buprenorphine and the pharmaceutical combination is administered intravenously.
  • the pharmaceutical combination is administered by injection, by pump infusion or by drip infusion.
  • the opioid is buprenorphine
  • the buprenorphine is administered orally.
  • the opioid is buprenorphine
  • the buprenorphine is administered as a tablet, a pill, a capsule or a sublingual.
  • the opioid is buprenorphine
  • the buprenorphine is
  • the buprenorphine is administered intravenously.
  • the opioid is buprenorphine
  • the buprenorphine is administered by injection, by pump infusion or by drip infusion.
  • the opioid is hydrocodone and the pharmaceutical combination is administered orally. In certain embodiments wherein the opioid is
  • the pharmaceutical combination is administered as a tablet, a pill, a capsule or a sublingual. In other embodiments wherein the opioid is hydrocodone, the hydrocodone is administered orally. In certain embodiments, the hydrocodone is administered as a tablet, a pill, a capsule or a sublingual. [0168] In some embodiments, the opioid is codeine and the pharmaceutical combination is administered orally. In certain embodiments wherein the opioid is codeine, the
  • the pharmaceutical combination is administered as a tablet, a pill, a capsule or a syrup.
  • the opioid is codeine
  • the codeine is administered orally.
  • the opioid is codeine
  • the codeine is administered a tablet, a pill, a capsule or a syrup.
  • the opioid is morphine and the pharmaceutical
  • the combination is administered orally.
  • the opioid is morphine
  • the pharmaceutical combination is administered as a tablet, a pill, or a capsule.
  • the opioid is morphine and the pharmaceutical combination is administered parenterally.
  • the pharmaceutical combination is administered intravenously, intramuscularly, epidurally, or subcutaneously.
  • the pharmaceutical combination is administered by injection, by pump infusion or by drip infusion.
  • the opioid is administered orally.
  • the opioid is administered as a tablet, a pill, or a capsule.
  • the opioid is administered intravenously, intramuscularly, epidurally, or subcutaneously.
  • the opioid is morphine
  • the morphine is administered by injection, by pump infusion or by drip infusion.
  • the opioid is methadone and the pharmaceutical combination is administered orally or intravenously.
  • the pharmaceutical combination is administered as a tablet, a capsule, a solution, a concentrate, a syrup, or a powder.
  • the opioid is methadone and the pharmaceutical combination is administered by injection, by pump infusion or by drip infusion.
  • the opioid is methadone
  • the methadone is administered orally.
  • the opioid is methadone
  • the methadone is administered as a tablet, a capsule, a solution, a concentrate, a syrup, or a powder.
  • the opioid is methadone
  • the methadone is administered intravenously.
  • the methadone is administered by injection, by pump infusion or by drip infusion.
  • the opioid is oxycodone and the pharmaceutical combination is administered orally.
  • the pharmaceutical combination is administered as a tablet, a capsule, or a solution.
  • the opioid is oxycodone
  • the oxycodone is administered orally.
  • the opioid is oxycodone
  • the oxycodone is administered as a tablet, a capsule, or a solution.
  • the opioid is hydromorphone and the pharmaceutical combination is administered orally. In certain embodiments wherein the opioid is
  • the pharmaceutical combination is administered as a tablet, or as a capsule.
  • the opioid is hydromorphone and the pharmaceutical combination is administered intravenously.
  • the pharmaceutical combination is administered by injection, by pump infusion, or by drip infusion.
  • the opioid is hydromorphone
  • the hydromorphone is administered orally.
  • the opioid is hydromorphone
  • the hydromorphone is administered as a tablet, or as a capsule.
  • the opioid is hydromorphone
  • the hydromorphone is administered intravenously.
  • the opioid is hydromorphone
  • the hydromorphone is administered by injection, by pump infusion, or by drip infusion.
  • the opioid is oxymorphone and the pharmaceutical combination is administered orally, parenterally, or rectally.
  • the pharmaceutical combination is administered as a tablet.
  • the opioid is oxymorphone
  • the pharmaceutical combination is administered by injection, by pump infusion or by drip infusion.
  • the opioid is oxymorphone
  • the pharmaceutical combination is administered as a suppository.
  • the opioid is oxymorphone
  • the oxymorphone is administered orally, parenterally, or rectally.
  • the opioid is oxymorphone
  • the oxymorphone is administered as a tablet.
  • the opioid is oxymorphone
  • the oxymorphone is administered parenterally. In certain embodiments wherein the opioid is oxymorphone, the oxymorphone is administered by injection, by pump infusion or by drip infusion. In yet other embodiments wherein the opioid is oxymorphone, the oxymorphone is administered rectally. In certain embodiments wherein the opioid is oxymorphone , the oxymorphone is administered as a suppository. [0174] In some embodiments, the opioid is tramadol and the pharmaceutical combination is administered orally. In certain embodiments wherein the opioid is tramadol, the
  • the pharmaceutical combination is administered as a tablet or a capsule.
  • the opioid is tramadol
  • the tramadol is administered orally.
  • the opioid is tramadol
  • the tramadol is administered as a tablet or a capsule.
  • the pharmaceutical combination may be administered according to a dosing regimen or schedule.
  • the dosing regimen for the pharmaceutical combinations of the present invention may vary depending upon several factors including, but not limited to, the pharmacodynamics characteristics of the cannabinoid and opioid present in the combination, the formulation or route of administration of the pharmaceutical combination, the nature and extent of the pain to be treated or prevented, and the medical history and condition of the subject in need thereof.
  • the pharmaceutical combination is administered once every hour, once every 2 hours, once every 3 hours, once every 4 hours, once every 5 hours, or once every 6 hours.
  • the pharmaceutical combination is administered at least once a day, at least twice a day, at least three times a day, at least four times a day, at least five times a day, or at least six times a day.
  • the pharmaceutical combination is administered at least ten times a day or at least 20 times a day.
  • the pharmaceutical combination is administered on a continuous basis.
  • the cannabinoid is dronabinol and the pharmaceutical combination is administered once ever once every hour, once every 2 hours, once every 3 hours, once every 4 hours, once every 5 hours, or once every 6 hours.
  • the cannabinoid is dronabinol and the pharmaceutical combination is administered at least once a day, at least twice a day, at least three times a day, at least four times a day, at least five times a day, or at least six times a day.
  • the cannabinoid is dronabinol and the pharmaceutical combination is administered at least ten times a day or at least 20 times a day.
  • the cannabinoid is dronabinol and the pharmaceutical combination is administered on a continuous basis.
  • the opioid is buprenorphine and pharmaceutical combination is administered once every 6 hours. In other embodiments, the opioid is buprenorphine and the pharmaceutical combination is administered at least once a day, at least twice a day, at least three times a day, or at least four times a day.
  • the opioid is hydrocodone and the pharmaceutical combination is administered once every 4 hours. In other embodiments, the opioid is hydrocodone and the pharmaceutical combination is administered at least once a day, at least twice a day, at least three times a day, at least four times a day, at least five times a day, or at least six times a day.
  • the opioid is codeine and the pharmaceutical combination is administered every 6 hours. In other embodiments, the opioid is codeine and the pharmaceutical combination is administered at least once a day, at least twice a day, at least three times a day, or at least four times a day.
  • the opioid is morphine and the pharmaceutical
  • the opioid is morphine and the pharmaceutical combination is administered at least once a day, at least twice a day, at least three times a day, at least four times a day, at least five times a day, or at least six times a day.
  • the opioid is oxycodone and the pharmaceutical combination is administered every 4 hours. In other embodiments, the opioid is oxycodone and the pharmaceutical combination is administered at least once a day, at least twice a day, at least three times a day, at least four times a day, at least five times a day, or at least six times a day.
  • the opioid is hydromorphone and the pharmaceutical combination is administered every 6 hours. In other embodiments, the opioid is
  • hydromorphone and the pharmaceutical combination is administered at least once a day, at least twice a day, at least three times a day, or at least four times a day.
  • the opioid is oxymorphone and the pharmaceutical combination is administered every 6 hours.
  • the opioid is oxymorphone and the pharmaceutical combination is administered at least once a day, at least twice a day, at least three times a day, or at least four times a day.
  • the opioid is methadone and the pharmaceutical combination is administered every 6 hours. In other embodiments, the opioid is methadone and the pharmaceutical combination is administered at least once a day, at least twice a day, at least three times a day, or at least four times a day.
  • the opioid is tramadol and the pharmaceutical combination is administered every 4 hours. In other embodiments, the opioid is tramadol and the pharmaceutical combination is administered at least once a day, at least twice a day, at least three times a day, at least four times a day, at least five times a day, or at least six times a day.
  • the dosing regimen may provide for a maximum cannabinoid dosage and maximum opioid dosage per day.
  • the amount of cannabinoid administered is less than or equal to 60 mg per day, or less than or equal to 50 mg per day.
  • the cannabinoid is dronabinol and the amount of dronabinol administered is less than or equal to 60 mg per day, or less than or equal to 50 mg per day.
  • the amount of opioid administered is less than or equal to 2400 micrograms per day, less than or equal to 60 mg per day, less than or equal to 64 mg per day, less than or equal to 80 mg per day, less than or equal to 120 mg per day, less than or equal to 180 mg per day or less than or equal to 240 mg per day. In certain embodiments, the amount of opioid administered is between 2400 micrograms per day and 240 mg per day. In certain embodiments, the amount of opioid administered is less than or equal 900 mg. In other embodiments, the amount of opioid administered is less than or equal to 1500 mg per day. In certain embodiments, the amount of opioid administered is less than or equal to 100 micrograms per day.
  • the opioid is buprenorphine and the amount of
  • buprenorphine administered is less than or equal to 64 mg per day.
  • the opioid is hydrocodone and the amount of hydrocodone administered is less than or equal to 900 mg per day.
  • the opioid is codeine and the amount of codeine administered is less than or equal to 900 mg per day.
  • the opioid is morphine and the amount of morphine administered is less than or equal to 900 mg per day.
  • the opioid is oxycodone and the amount of oxycodone administered is less than or equal to 900 mg per day.
  • the opioid is methadone and the amount of methadone administered is less than or equal to 1500 mg per day.
  • the opioid is hydromorphone and the amount of hydromorphone administered is less than or equal to 1500 mg per day.
  • the opioid is oxymorphone and the amount of
  • oxymorphone administered is less than or equal to 1500 mg per day.
  • the opioid is tramadol and the amount of tramadol administered is less than or equal to 1500 mg per day.
  • the subject in need thereof is a mammal.
  • the subject in need thereof is a human.
  • the subject in need thereof may also be referred to as the patient or the recipient.
  • the fixed-dose pharmaceutical combinations and methods for pain management comprising administering said combinations are especially suitable for subjects or patients identified as belonging to a particular population sub-type.
  • the subject in need thereof suffers from opioid refractory pain.
  • the pain is refractory or resistant to opioid treatment therapy alone.
  • the subject in need thereof having pain refractory to opioid treatment therapy suffers from opioid use disorder, opioid-induced hyperalgesia, or opioid tolerance drift.
  • the subject in need thereof has an opioid use disorder (OUD) or a substance use disorder (SUD).
  • a use disorder may also be referred to as an“addiction”.
  • Opioid use disorder is a problematic pattern of opioid use that leads to clinically significant distress or impairment and is characterized by the continued and escalating use of opioids despite repeated attempts by the patient to decrease use, and despite significant adverse social, economic, and behavioral consequences.
  • the subject in need thereof has opioid use disorder.
  • the subject may be described as being“addicted to” or having a use disorder associated with one or more opioids.
  • the opioid use disorder may be associated with one or more opioids.
  • the subject in need thereof has an opioid use disorder, wherein the opioid disorder is associated with an opioid selected from the group consisting of selected from the group consisting of anilopam, pentazocine, dihydroetorphine, phenazocine, sufentanil, codeine, alfentanil, meperidine, morphine, propoxyphene, morphine sulfate ester, tramadol, hydromorphone, buprenorphine, oxymorphone, levorphanol, methadone, L- acetylmethadol, oxycodone, etorphine, hydrocodone, normethadone, remifentanil, noroxycodone, dihydrocodeine, norlevorphanol, ethylmorphine, nalbuphine, hydromorphine, normorphine, dihydroetorphine, and butorphanol.
  • an opioid selected from the group consisting of selected from the group consisting of anilopam, pent
  • the subject in need thereof has opioid use disorder, wherein the opioid use disorder is associated with morphine, heroin, codeine, oxycodone, hydrocodone, oxymorphone, hydromorphone, tramadol, or methadone.
  • the opioid use disorder is associated with oxycodone.
  • the opioid use disorder is associated with hydrocodone.
  • the opioid use disorder is associated with methadone.
  • the subject in need thereof has or suffering from opioid-related side effects or adverse effects.
  • the subject in need thereof suffers from opioid-related side effects, wherein the opioid-related side effect is opioid-induced constipation (OIC), opioid-induced hyperalgesia (OIH), or opioid tolerance drift (OTD), or any combination thereof.
  • OIC opioid-induced constipation
  • OIH opioid-induced hyperalgesia
  • OTD opioid tolerance drift
  • opioid-induced hyperalgesia and opioid tolerance drift are highly correlated with the opioid use disorder.
  • OIH is a heightened sensitivity to pain that is induced by chronic opioid therapy.
  • OTD is an escalation toward higher and higher doses of opioids in order to achieve adequate analgesia.
  • opioid-induced hyperalgesia and opioid tolerance drift may respond differently to opioid treatment regimens although both result in an overall reduced analgesic response to opioid treatment. For example, an increase in opioid dosage amount may be sufficient to overcome OTD, but an increase in opioid dosage amount in may intensify pain for a patient suffering from OIH, thereby worsening the patient’s condition.
  • the subject in need thereof has an opioid use disorder, opioid-induced hyperalgesia, opioid tolerance drift, or any combination thereof.
  • the subject in need thereof has an opioid use disorder and opioid-induced hyperalgesia.
  • the subject in need thereof has an opioid use disorder and opioid tolerance drift.
  • the subject in need thereof has opioid-induced hyperalgesia and opioid tolerance drift.
  • the subject in need thereof has opioid use disorder, opioid-induced hyperalgesia and opioid tolerance drift.
  • the subject in need thereof suffers from hepatic
  • NSAIDs non-steroidal anti-inflammatory drugs
  • the subject in need thereof suffers from hepatic impairments.
  • the subject in need thereof suffers from intolerance to non-steroidal anti inflammatory drugs.
  • the subject in need thereof has hepatic impairments related to NSAID-intolerance, opioid use disorder, substance use disorder, opioid-induced constipation, opioid refractory pain, opioid-induced hyperalgesia, or opioid tolerance drift, or any combination thereof.
  • the pain to be managed by the methods of the present disclosure can be characterized by the rate of onset and/or duration.
  • the pain is acute or chronic pain.
  • the pain of the method of the present disclosure can be characterized by intensity, or severity.
  • the pain is mild pain, moderate pain, or severe pain. It should be recognized that the pain to be treated or prevented by the method of the present disclosure may be characterized as any combination of the above pain types.
  • the pain is an acute mild pain, an acute moderate pain, or an acute severe pain.
  • the pain is a chronic mild pain, a chronic moderate pain, or a chronic severe pain.
  • the pain is postoperative pain, refractory neuropathic or nociceptive pain, or refractory malignant pain.
  • the pain is postoperative pain.
  • the pain is refractory neuropathic or nociceptive pain.
  • the pain is refractory malignant pain.
  • the pain is psychogenic pain, neurological pain, nociplastic pain, algopathic pain, pain related to cough, and/or pain related to gastrointestinal maladies.
  • the efficacy of the present methods as described herein may be characterized by the extent of pain intensity or other symptoms and secondary effects.
  • the ratings disclosed herein can be employed to assess a patient’s level of pain before, during and after treatment and thereby determine the efficacy of the treatment.
  • the measurement of pain intensity and other symptoms or secondary effects include the scales, checklists, surveys described herein, in addition to other qualitative and quantitative measures known in the art.
  • pain scales having different numeric ranges (0-4 vs 0-10), or different rating types (e.g. numeric vs. descriptor) may be converted interchangeably by methods known in the art.
  • pain intensity is measured by at least one pain scale.
  • the at least one pain scale is selected from the group consisting of the visual analog scale (VAS), the verbal numerical rating scale (VNRS), the verbal descriptor scale (VDS) and the brief pain inventory.
  • pain intensity is measured by the verbal numerical rating scale. With respect to the verbal numerical rating scale (0-10), a higher rating or score equates to higher pain intensity.
  • the present disclosure provides a method wherein administration of the pharmaceutical combination results in a pain intensity rating of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • administration of the pharmaceutical combination results in a pain intensity rating of at most 1, at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8 or at most 9.
  • the present methods result in a pain intensity rating of between 0 and 1, between 0 and 2, between 0 and 3, between 0 and 4, between 0 and 5, between 0 and 6, between 0 and 7, between 0 and 8, between 0 and 9, between 0 and 10, between 1 and 2, between 1 and 3, between 1 and 4, between 1 and 5, between 1 and 6, between 1 and 7, between 1 and 8, between 1 and 9, between 1 and 10, between 2 and 3, between 2 and 4, between 2 and 5, between 2 and 6, between 2 and 7, between 2 and 8, between 2 and 9, between 2 and 10, between 3 and 4, between 3 and 5, between 3 and 6, between 3 and 7, between 3 and 8, between 3 and 9, between 3 and 10, between 4 and 5, between 4, and 6, between 4 and 7, between 4 and 8, between 4 and 9, between 4 and 10, between 5 and 6, between 5 and 7, between 5 and 8, between 5 and 9, between 5 and 10, between 6 and 7, between 6 and 8, between 6 and 9, between 6 and 10, between 7 and 8, between 7 and 9, between 7 and 10, between 8 and 9, between 8 and 10, or between 9 and 10.
  • pain intensity is measured by the verbal descriptor scale.
  • the pain intensity measured by the verbal descriptor is characterized as no pain, mild pain, moderate pain, severe pain, extreme pain or worst pain possible.
  • pain intensity is measured by the brief pain inventory.
  • pain is measured by the pain relief scale. With respect to the pain relief scale (0-10), a higher rating or score equates to greater pain relief experienced by the subject.
  • the present disclosure provides a method wherein administration of the pharmaceutical combination results in a pain relief rating of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • the present methods result in a pain relief rating of at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8 or at least 9.
  • the present methods result in a pain relief rating of between 0 and 1, between 0 and 2, between 0 and 3, between 0 and 4, between 0 and 5, between 0 and 6, between 0 and 7, between 0 and 8, between 0 and 9, between 0 and 10, between 1 and 2, between 1 and 3, between 1 and 4, between 1 and 5, between 1 and 6, between 1 and 7, between 1 and 8, between 1 and 9, between 1 and 10, between 2 and 3, between 2 and 4, between 2 and 5, between 2 and 6, between 2 and 7, between 2 and 8, between 2 and 9, between 2 and 10, between 3 and 4, between 3 and 5, between 3 and 6, between 3 and 7, between 3 and 8, between 3 and 9, between 3 and 10, between 4 and 5, between 4 and 6, between 4 and 7, between 4 and 8, between 4 and 9, between 4 and 10, between 5 and 6, between 5 and 7, between 5 and 8, between 5 and 9, between 5 and 10, between 6 and 7, between 6 and 8, between 6 and 9, between 6 and 10, between 7 and 8, between 7 and 9, between 7 and 10, between 8 and 9, between 8 and 10, or between 9 and 10.
  • Pain may also be characterized by pain bothersomeness.
  • a lower bothersomeness rating or score equates to greater or improved quality of life.
  • administration of the pharmaceutical combination results in a pain bothersomeness rating of 0, 1, 2, 3 or 4.
  • the method for pain management results in a pain bothersomeness rating of at most 4, at most 3, at most 2 or at most 1.
  • the present method results in a pain bothersomeness rating between 0 and 2, between 0 and 3, between 0 and 4, between 1 and 3, between 1 and 4, or between 2 and 4.
  • the method is characterized by the patient satisfaction according to the medication satisfaction scale.
  • the medication satisfaction scale (0-10)
  • a higher score or rating equates to greater patient satisfaction with treatment.
  • administration of the pharmaceutical combination results in a patient satisfaction rating of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 on the medication satisfaction scale.
  • the method results in a patient satisfaction rating of at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8 or at least 9 on the medication satisfaction scale.
  • the efficacy of the present methods is measured by the hospital and anxiety depression scale (HADS), the side-effect checklist (29-item), the RAND health survey (36-item), or the MOS sleep scale.
  • HADS hospital and anxiety depression scale
  • side-effect checklist 29-item
  • RAND health survey 36-item
  • MOS sleep scale the MOS sleep scale
  • the present disclosure provides for a method for pain management, wherein the method reduces the incidence and/or severity of opioid use disorder.
  • the present disclosure provides for a method of treating opioid-induced hyperalgesia and/or opioid tolerance drift in a patient in need thereof. It should be recognized that improvements in opioid-related conditions or reductions of side effects may be determined relative to a baseline measurement. In some embodiments, the baseline measurement is a measurement taken before initiation of pain management by the methods disclosed. Pain Reduction and Pain Relief
  • pain intensity is reduced from baseline.
  • pain intensity is reduced from baseline according to a pain intensity score or rating.
  • the pain intensity rating is reduced by at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, or at least 9 from baseline on the pain intensity verbal numerical descriptor scale.
  • the pain intensity rating is reduced by 1, by 2, by 3, by 4, by 5, by 6, by 7, by 8, by 9 or by 10 on the pain intensity scale.
  • the pain intensity is reduced by between 1 and 2, between 1 and 3, between 1 and 4, between 1 and 5, between 1 and 6, between 1 and 7, between 1 and 8, between 1 and 9, between 1 and 10, between 2 and 3, between 2 and 4, between 2 and 5, between 2 and 6, between 2 and 7, between 2 and 8, between 2 and 9, between 2 and 10, between 3 and 4, between 3 and 5, between 3 and 6, between 3 and 7, between 3 and 8, between 3 and 9, between 3 and 10, between 4 and 5, between 4 and 6, between 4 and 7, between 4 and 8, between 4 and 9, between 4 and 10, between 5 and 6, between 5 and 7, between 5 and 8, between 5 and 9, between 5 and 10, between 6 and 7, between 6 and 8, between 6 and 9, between 6 and 10, between 7 and 8, between 7 and 9, between 7 and 10, between 8 and 9, between 8 and 10 or between 9 and 10 on the pain intensity verbal numerical descriptor scale.
  • pain intensity is reduced by at least about 5 percent, at least about 10 percent, at least about 15 percent, at least about 20 percent, at least about 25 percent, at least about 30 percent, at least about 35 percent, at least about 40 percent, at least about 40 percent, at least about 45 percent, or at least about 50 percent, at least about 55 percent, at least about 60 percent, at least about 65 percent, at least about 70 percent, at least about 75 percent, at least about 80 percent, at least about 85 percent, at least about 90 percent, or at least about 95 percent from baseline.
  • pain intensity is reduced by at least about 30 percent from baseline. In other embodiments, the pain intensity is reduced by at least about 20 percent from baseline.
  • pain intensity is reduced by between about 5 percent and about 95 percent, between about 5 percent and about 90 percent, between about 5 percent and about 85 percent, between about 5 percent and about 80 percent, between about 5 percent and about 75 percent, between about 5 percent and about 70 percent, between about 5 percent and about 65 percent, between about 5 percent and about 60 percent, between about 5 percent and about 55 percent, between about 5 percent and about 50 percent, between about 5 percent and about 45 percent, between about 5 percent and about 40 percent, between about 5 percent and about 35 percent, between about 5 percent and about 30 percent, between about 5 percent and about 25 percent, between about 5 percent and about 20 percent, between about 5 percent and about 15 percent, between about 5 percent and about 10 percent, between about 10 percent and about 95 percent, between about 10 percent and about 90 percent, between about 10 percent and about 85 percent, between about 10 percent and about 80 percent, between about 10 percent and about 75 percent, between about 10 percent and about 70 percent, between about 10 percent and about 65 percent, between about 10 percent and about 60 percent, between about 10 percent and about 55
  • the pain bothersomeness rating is reduced by at least 1, at least 2, or at least 3 from baseline on the pain bothersomeness scale. In other embodiments, the pain bothersomeness is reduced by 1, by 2, by 3, or by 4 from baseline on the pain bothersomeness scale. In yet other embodiments, the pain bothersomeness rating is reduced by between 1 and 2, between 1 and 3, between 1 and 4, between 2 and 3, between 2 and 4, or between 3 and 4 from baseline on the pain
  • the patient satisfaction is increased by at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, or at least 9 from baseline on the medication satisfaction scale. In other embodiments, patient satisfaction is increased by 1, by 2, by 3, by 4, by 5, by 6, by 7, by 8, by 9 or by 10 from baseline on the medication satisfaction scale.
  • the patient satisfaction is increased by between 1 and 2, between 1 and 3, between 1 and 4, between 1 and 5, between 1 and 6, between 1 and 7, between 1 and 8, between 1 and 9, between 1 and 10, between 2 and 3, between 2 and 4, between 2 and 5, between 2 and 6, between 2 and 7, between 2 and 8, between 2 and 9, between 2 and 10, between 3 and 4, between 3 and 5, between 3 and 6, between 3 and 7, between 3 and 8, between 3 and 9, between 3 and 10, between 4 and 5, between 4 and 6, between 4 and 7, between 4 and 8, between 4 and 9, between 4 and 10, between 5 and 6, between 5 and 7, between 5 and 8, between 5 and 9, between 5 and 10, between 6 and 7, between 6 and 8, between 6 and 9, between 6 and 10, between 7 and 8, between 7 and 9, between 7 and 10, between 8 and 9, between 8 and 10 or between 9 and 10 from baseline on the medication satisfaction scale.
  • the pain relief rating is increased by at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, or at least 9 from baseline on the pain relief scale. In other embodiments, the pain relief rating is increased by 1, by 2, by 3, by 4, by 5, by 6, by 7, by 8, by 9 or by 10 from baseline on the pain relief scale.
  • the pain relief rating is increased by between 1 and 2, between 1 and 3, between 1 and 4, between 1 and 5, between 1 and 6, between 1 and 7, between 1 and 8, between 1 and 9, between 1 and 10, between 2 and 3, between 2 and 4, between 2 and 5, between 2 and 6, between 2 and 7, between 2 and 8, between 2 and 9, between 2 and 10, between 3 and 4, between 3 and 5, between 3 and 6, between 3 and 7, between 3 and 8, between 3 and 9, between 3 and 10, between 4 and 5, between 4 and 6, between 4 and 7, between 4 and 8, between 4 and 9, between 4 and 10, between 5 and 6, between 5 and 7, between 5 and 8, between 5 and 9, between 5 and 10, between 6 and 7, between 6 and 8, between 6 and 9, between 6 and 10, between 7 and 8, between 7 and 9, between 7 and 10, between 8 and 9, between 8 and 10 or between 9 and 10 from baseline on the pain relief scale.
  • Improvements in opioid-related side effects as a result of the disclosed methods may also be characterized by reductions in opioid dosage amounts from the standard opioid dose, and/or frequency of administration from baseline using the standard opioid dose, and/or reduction in opioid-related side effects and/or pain as a result of the synergistic quality of the pharmaceutical combination at the same dose of the opioid.
  • the amount of opioid present in the pharmaceutical combination is at least about 1 microgram less than, at least about 2 micrograms less than, at least 2.5 micrograms less than, at least about 4 micrograms less than, at least about 5 micrograms less than, at least about 7.5 micrograms less than, at least about 10 micrograms less than, at least 20 micrograms less than, at least 50 micrograms less than, at least 100 micrograms less than, at least 150 micrograms less than, at least 200 micrograms less than, at least 250 micrograms less than, at least 300 micrograms less than, at least 350 micrograms less than, at least 400 micrograms less than, at least 450 micrograms less than, at least 500 micrograms less than, at least 750 micrograms less than, at least about 1 mg less than, at least about 2 mg less than, at least about 3 mg less than, at least about 4 mg less than, at least about 5 mg less than, at least about 6 mg less than, at least about 7 mg less than, at
  • the amount of opioid present in the pharmaceutical combination is between about 1 microgram and about 1 mg less than, between about 1 microgram and about 750 micrograms less than, between about 1 microgram and about 500 micrograms less than, between about 1 microgram and about 450 micrograms less than, between about 1 microgram and about 400 micrograms less than, between about 1 microgram and about 350 micrograms less than, between about 1 microgram and about 300 micrograms less than, between about 1 microgram and about 250 micrograms less than, between about 1 microgram and about 200 micrograms less than, between about 1 microgram and about 150 micrograms less than, between about 1 microgram and about 100 micrograms less than, between about 1 microgram and about 50 micrograms less than, between about 1 microgram and about 20 micrograms less than, between about 1 microgram and about 10 micrograms less than, between about 1 microgram and about 7.5 micrograms less than, between about 1 microgram and about 5 micrograms less than, between about 1 microgram and about 4 micrograms less than, between about 1 microgram
  • the amount of opioid present in the pharmaceutical combination is between about 1 mg and about 20 mg less than, between about 1 mg and about 15 mg less than, between about 1 mg and about 12 mg less than, between about 1 mg and about 10 mg less than, between about 1 mg and about 9 mg less than, between about 1 mg and about 8 mg less than, between about 1 mg and about 7 mg less than, between about 1 mg and about 6 mg less than, between about 1 mg and about 5 mg less than, between about 1 mg and about 4 mg less than, between about 1 mg and about 3 mg less than, between about 1 mg and about 2 mg less than, between about 2 mg and about 20 mg less than, between about 2 mg and about 15 mg less than, between about 2 mg and about 12 mg less than, between about 2 mg and about 10 mg less than, between about 2 mg and about 9 mg less than, between about 2 mg and about 8 mg less than, between about 2 mg and about 7 mg less than, between about 2 mg and about 6 mg less than, between about 2 mg and about 5 mg less than, between about 2 mg and about 4 mg less than, between about
  • the amount of opioid present in the pharmaceutical combination is between about 20 mg and about 200 mg less than, between about 20 mg and about 180 mg less than, between about 20 mg and about 160 mg less than, between about 20 mg and about 140 mg less than, between about 20 mg and about 120 mg less than, between about 20 mg and about 100 mg less than, between about 20 mg and about 90 mg less than, between about 20 mg and about 80 mg less than, between about 20 mg and about 70 mg less than, between about 20 mg and about 60 mg less than, between about 20 mg and about 50 mg less than, between about 20 mg and about 45 mg less than, between about 20 mg and about 40 mg less than, between about 20 mg and about 35 mg less than, between about 20 mg and about 30 mg less than, between about 20 mg and about 25 mg less than, between about 25 mg and about 200 mg less than, between about 25 mg and about 180 mg less than, between about 25 mg and about 160 mg less than, between about 25 mg and about 140 mg less than, between about 25 mg and about 120 mg less than, between about 25 mg and about 100 mg less than, between about
  • the amount of opioid present in the pharmaceutical combination is at least about 2 percent less than, at least about 5 percent less than, at least about 7 percent less than, at least about 10 percent less than, at least about 12 percent less than, at least about 15 percent less than, at least about 17 percent less than, at least about 20 percent less than, at least about 22 percent less than, at least about 25 percent less than, at least about 27 percent less than, at least about 30 percent less than, at least about 32 percent less than, at least about 35 percent less than, at least about 37 percent less than, at least about 40 percent less than, at least about 45 percent less than, at least about 50 percent less than, at least about 55 percent less than, at least about 60 percent less than, at least about 65 percent less than, at least about 70 percent less than, at least about 75 percent less than, at least about 80 percent less than, at least about 85 percent less than, at least about 90 percent less than, or at least about 95 percent less than the standard opioid dose.
  • the amount of opioid present in the pharmaceutical combination is between about 2 percent and about 5 percent less than, between about 5 percent and about 10 percent less than, between about 10 percent and about 20 percent less than, between about 20 percent and about 30 percent less than, between about 30 percent and about 40 percent less than, between about 40 percent and about 50 percent less than, between about 50 percent and about 60 percent less than, between about 60 percent and about 70 percent less than, between about 70 percent and about 80 percent less than, between about 80 percent and about 90 percent less than, or between about 90 percent and about 95 percent less than the standard opioid dose.
  • the amount of opioid present in the pharmaceutical is between about 2 percent and about 5 percent less than, between about 5 percent and about 10 percent less than, between about 10 percent and about 20 percent less than, between about 20 percent and about 30 percent less than, between about 30 percent and about 40 percent less than, between about 40 percent and about 50 percent less than, between about 50 percent and about 60 percent less than, between about 60 percent and about 70 percent less than, between about 70 percent and about 80 percent less than, between about 80 percent and about 90 percent
  • the combination is at least about 30 percent less than the standard opioid dose. In other embodiments, the amount of opioid present in the pharmaceutical combination is at least about 20 percent less than the standard opioid dose.
  • the frequency of administration from baseline may be characterized as decreases in the number of times of per day the pharmaceutical combination is administered.
  • the number of times per day the pharmaceutical combination is administered is reduced by one time, by two times, by three times, by four times, by five times, by six times, by seven times, by eight times, by nine times, by ten times, by eleven times, or by twelve times.
  • the number of times per day the pharmaceutical combination is administered is reduced by one time, by two times, by three times, by four times, by five times or by six times.
  • the frequency of administration is expressed as a percentage of the baseline frequency. In some embodiments, the frequency of administration is about 95 percent, about 90 percent, about 85 percent, about 80 percent, about 75 percent, about 70 percent, about 65 percent, about 60 percent, about 55 percent, about 50 percent, about 45 percent, about 40 percent, about 35 percent, about 30 percent, about 25 percent, about 20 percent, about 15 percent, or about 10 percent of baseline frequency.
  • the frequency of administration is between about 10 percent and about 95 percent, between about 10 percent and about 90 percent, between about 10 percent and about 85 percent, between about 10 percent and about 80 percent, between about 10 percent and about 75 percent, between about 10 percent and about 70 percent, between about 10 percent and about 65 percent, between about 10 percent and about 60 percent, between about 10 percent and about 55 percent, between about 10 percent and about 50 percent, between about 10 percent and about 45 percent, between about 10 percent and about 40 percent, between about 10 percent and about 35 percent, between about 10 percent and about 30 percent, between about 10 percent and about 25 percent, between about 10 percent and about 20 percent, between about 10 percent and about 15 percent, between about 15 percent and about 95 percent, between about 15 percent and about 90 percent, between about 15 percent and about 85 percent, between about 15 percent and about 80 percent, between about 15 percent and about 75 percent, between about 15 percent and about 70 percent, between about 15 percent and about 65 percent, between about 15 percent and about 60 percent, between about 15 percent and about 55 percent, between about 15 percent and about 50 percent, between about 10 percent and about
  • the frequency of administration is reduced by a percentage of the baseline frequency.
  • the frequency of administration is reduced by at least about 5 percent, by at least about 10 percent, by at least about 15 percent, by at least about 20 percent, by at least about 25 percent, by at least about 30 percent, by at least about 35 percent, by at least about 40 percent, by at least about 45 percent, by at least about 50 percent, by at least about 55 percent, by at least about 60 percent, by at least about 65 percent, by at least about 70 percent, by at least about 75 percent, by at least about 80 percent, by at least about 85 percent, by at least about 90 percent, or by at least about 95 percent from baseline.
  • the frequency of administration is reduced by at least about 30 percent from baseline. In other
  • the frequency of administration is reduced by at least about 20 percent from baseline.
  • the frequency of administration is reduced by between about 5 percent and about 95 percent, between about 5 percent and about 90 percent, between about 5 percent and about 85 percent, between about 5 percent and about 80 percent, between about 5 percent and about 75 percent, between about 5 percent and about 70 percent, between about 5 percent and about 65 percent, between about 5 percent and about 60 percent, between about 5 percent and about 55 percent, between about 5 percent and about 50 percent, between about 5 percent and about 45 percent, between about 5 percent and about 40 percent, between about 5 percent and about 35 percent, between about 5 percent and about 30 percent, between about 5 percent and about 25 percent, between about 5 percent and about 20 percent, between about 5 percent and about 15 percent, between about 5 percent and about 10 percent, between about 10 percent and about 95 percent, between about 10 percent and about 90 percent, between about 10 percent and about 85 percent, between about 10 percent and about 80 percent, between about 10 percent and about 75 percent, between about 10 percent and about 70 percent, between about 10 percent and about 65 percent, between about 10 percent and about 60 percent, between about 10 percent and
  • the time between doses is increased by at least about 15 minutes, by at least about 30 minutes, by at least about 45 minutes, by at least about 1 hour, by at least about 1.5 hours, by at least about 2 hours, by at least about 3 hours, by at least about 4 hours, by at least about 5 hours, by at least about 6 hours, by at least about 8 hours, by at least about 10 hours, by at least about 12 hours, by at least about 14 hours, by at least about 16 hours, by at least about 18 hours, by at least about 20 hours, by at least about 22 hours, or by at least about 24 hours.
  • the time between doses is increased by between about 15 minutes and about 24 hours, between about 15 minutes and about 22 hours, between about 15 minutes and about 20 hours, between about 15 minutes and about 18 hours, between about 15 minutes and about 16 hours, between about 15 minutes and about 14 hours, between about 15 minutes and about 12 hours, between about 15 minutes and about 10 hours, between about 15 minutes and about 8 hours, between about 15 minutes and about 6 hours, between about 15 minutes and about 5 hours, between about 15 minutes and about 4 hours, between about 15 minutes and about 3 hours, between about 15 minutes and about 2 hours, between about 15 minutes and about 1 hour, between about 15 minutes and about 45 minutes, between about 15 minutes and about 30 minutes, between about 30 minutes and about 24 hours, between about 30 minutes and about 22 hours, between about 30 minutes and about 20 hours, between about 30 minutes and about 18 hours, between about 30 minutes and about 16 hours, between about 30 minutes and about 14 hours, between about 30 minutes and about 12 hours, between about 30 minutes and about 10 hours, between about 30 minutes and about 8 hours, between about 30 minutes and about 6 hours, between about 15
  • the present disclosure provides for a method of pain management in subject in need thereof, wherein:
  • the amount of opioid present in the pharmaceutical combination is at least about 20 percent less than the standard opioid dose
  • the present disclosure provides for a method of pain management in subject in need thereof, wherein:
  • the pain intensity is reduced by at least 20 percent from baseline;
  • the amount of opioid present in the pharmaceutical combination is at least about 20 percent less than the standard opioid dose;
  • a step of weaning, tapering or stepping-down of the pharmaceutical combination can involve a reduction in the amount of opioid present in the pharmaceutical combination, a reduction in the frequency of administration of the pharmaceutical combination or a change and/or substitution in the opioid present in the pharmaceutical combination to a less-addictive opioid.
  • the method further comprises administering a second pharmaceutical fixed-dose combination comprising dronabinol and an opioid or a combination of opioids.
  • the method comprises
  • the first opioid and the second opioid are the same or different.
  • the first opioid and the second opioid or combination of opioids are selected from the group consisting of buprenorphine, hydrocodone, codeine, morphine, oxycodone, tramadol, oxymorphone, hydromorphone, and methadone.
  • the first opioid is selected from the group consisting of buprenorphine, hydrocodone, codeine, morphine, oxycodone, tramadol, oxymorphone, hydromorphone and methadone, and the second opioid is buprenorphine.
  • the first opioid and the second opioid are the same.
  • the first opioid is buprenorphine, and the second opioid is buprenorphine.
  • the first opioid is hydrocodone
  • the second opioid is hydrocodone.
  • the first opioid is codeine
  • the second opioid is codeine.
  • the first opioid is morphine
  • the second opioid is morphine.
  • the first opioid is oxycodone, and the second opioid is oxycodone.
  • the first opioid is methadone, and the second opioid is methadone.
  • the first opioid is tramadol, and the second opioid is tramadol.
  • the first opioid is hydromorphone, and the second opioid is hydromorphone.
  • the first opioid is oxymorphone, and the second opioid is oxymorphone.
  • the first opioid and the second opioid are different.
  • the first opioid is hydrocodone, and the second opioid is buprenorphine.
  • the first opioid is codeine, and the second opioid is buprenorphine.
  • the first opioid is morphine, and the second opioid is buprenorphine.
  • the first opioid is oxycodone, and the second opioid is
  • the first opioid is methadone, and the second opioid is buprenorphine. In some embodiments, the first opioid is tramadol, and the second opioid is buprenorphine. In other embodiments, the first opioid is hydromorphone, and the second opioid is buprenorphine. In still other embodiments, the first opioid is oxymorphone, and the second opioid is buprenorphine.
  • the second frequency of administration is less than the first frequency of administration, the second dosage amount is less than the first dosage amount, or a combination thereof.
  • Table 1 provides a summary of dosages, formulations, routes of administration and indications for some exemplary pharmaceutical combinations of the present disclosure. The summary should not, however, be construed as limiting the scope of the present disclosure. It is understood that the summary provided is for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. Table 1
  • a pharmaceutical combination comprising:
  • the pharmaceutical combination of embodiment 17, wherein the opioid is methadone and the amount of methadone present is between about 0.5 mg and less than 2.5 mg. 29.
  • the pharmaceutical combination of embodiment 28, wherein the amount of methadone present is about 0.5 mg, about 0.7 mg, about 1 mg, about 1.5 mg, or about 2 mg.
  • a method for pain management comprising administering to a subject in need thereof the pharmaceutical combination of any one of embodiments 1-34.
  • the pain intensity is reduced by at least about 10 percent, at least about 20 percent, at least about 30 percent, at least about 40 percent, at least about 50 percent, at least about 60 percent, or at least about 70 percent from a baseline pain intensity;
  • the amount of opioid present in the pharmaceutical combination is at least about 10 percent, at least about 20 percent, at least about 30 percent, at least about 40 percent, at least about 50 percent, at least about 60 percent, or at least about 70 percent less than the standard opioid dose prescribed for the subject;
  • the frequency of administration is reduced by at least about 10 percent, at least about 20 percent, at least about 30 percent, at least about 40 percent, at least about 50 percent, at least about 60 percent, or at least about 70 percent from a baseline administration frequency; or
  • administration frequency is the average dosing frequency used by the subject on the standard dose of the same opioid administered on its own.
  • Phase I The efficacy of a dronabinol-opioid fixed dose pharmaceutical combination is assessed in a 6-week study (Phase I) and follow-up, one-year longitudinal extension study (Phase II) evaluating the efficacy of the disclosed fixed-dose combination for opioid-sparing effect in patients receiving standalone opioid treatment therapy for pain management.
  • Table 2 shows the schedule of activities for Phases I and II.
  • the primary endpoints are, with respect to the baseline set from the first week of Phase I, a reduction in pain intensity experienced by patients and reduction in the absolute daily dose of opioid administered to the patient, and/or increase in the duration of time between doses. Additional evaluative criteria include changes in pain history, intensity, location; occurrence of depression and generalized anxiety or changes in depression and generalized anxiety from baseline; change in overall quality of life from baseline; change in quality of sleep from baseline; or change in pain relief experience from baseline.
  • Sample Size 50 participants (10 for dronabinol+buprenorphine treatment; 40 for dronabinol+non-buprenorphine opioid);
  • Chronic pain that may be related to treatment-refractory pain, or opioid use disorder, or opioid-induced hyperalgesia, or opioid-induced tolerance.
  • Study Screening & Enrollment Individuals are screened and selected from a pool of a potential participants suffering chronic, treatment-refractory pain related to opioid use disorder, opioid-induced hyperalgesia or opioid-induced tolerance. The participants are assigned to one of two treatment arms: (1) co-administration of dronabinol and
  • buprenorphine and (2) co-administration of dronabinol and another non-buprenorphine opioid.
  • Phase I Visit 1 - Baseline Visit: On Day 1 of Week 1, participants attend an enrollment visit. During the enrollment visit, participants complete a battery assessment in which they are required to:
  • Dronabinol placebo daily along with their regular prescribed opioids, continuing to track opioid dose, time between opioid doses, and level of pain intensity.
  • Participants will take the Dronabinol study-drug daily along with their regular prescribed opioids, continuing to track opioid dose, time between opioid doses, and level of pain intensity.
  • the dose of Dronabinol will be titrated up to a stabilized level of 30 mg per day, over 6 days, in 5 mg cumulative increments.
  • BPI Pain and quality of life measures: Brief Pain Inventory (BPI), The Hospital and Anxiety Depression Scale (HADS), The Side Effect Checklist 29-item, RAND 36-Item Health Survey, The MOS Sleep Scale.;
  • Phase I, Visit 3 - End of Phase I Study Visit On Day 42 of Week 6, participants will complete the same assessment battery used and examinations performed during the baseline visit.
  • Phase II End of Phase I and Beginning of Phase II: At the termination of the 6-week study, participants are invited to enter a longitudinal extension study (Phase II), examining efficacy of the fixed-dose combination for continued opioid-sparing effects and
  • the combination treatment is provided as a month-long supply of the combination treatment according to the treatment arm assignment. Participants continue to record opioid dose, time between doses, and pain intensity (on the pain intensity scale, 0-10) on a daily basis. The participants continue to provide an assessment of pain intensity (on the pain intensity scale, 0-10) daily, via SMS messaging.
  • Participants attend monthly follow-up visits to obtain refills of the combination treatment and complete pain intensity scale, pain relief scale, pain bothersomeness scale and medication satisfaction scale assessments. Participants attend a yearly check-up visit to complete the full battery assessment as conducted on the baseline visit of Phase I.
  • the primary endpoints of pain intensity, opioid use, and opioid use frequency are captured daily by patient self-report using a specialized Opioid-Sparing Diary.
  • the secondary endpoints measuring change from baseline in: pain history, intensity, location, relief, life interference, mood, depression and generalized anxiety, presence or absence of side effects associated with the intervention, overall quality of life, quantity and quality of sleep, average weekly distance traveled, average weekly caloric expenditure, satisfaction with medication, number of bowel movements, severity of opioid-induced constipation, possible opioid misuse, severity of opioid-related side effects, pain-related healthcare expenditures from baseline, are recorded using a digital tablet collection device, with the exception of the Mood Scale (0-10), Sleep Self-Report (0-10), and Bowel Movement Inventory (#), which are captured daily using the Opioid-Sparing Diary (OSD), and the Sleep Tracker, Distance Tracker, and Calorie Tracker, which are captured using the FITBIT Wearable Technology device that measures health and fitness data.
  • OSD Opioid
  • the outcome measures used are: Brief Pain Inventory (BPI), Mood Scale (0-10), Hospital and Anxiety Depression Scale (HADS), Side Effect Checklist 29-item, RAND Health Survey 36-item, MOS Sleep Scale, Sleep Self Report (0-10), FITBIT Sleep Tracker, FITBIT Distance Tracker, FITBIT Calorie Tracker, Treatment Satisfaction Questionnaire for Medication (TSQM), Bowel Movement 24-Hour Log (#), Bowel Function Index - Revised (BFI-R), Current Opioid Misuse Measure
  • Sample Size 280 (40 each for subgroups: 1) Oxycodone, 2) Mixed Opioids, 3) Hydrocodone + Acetaminophen, 4) Morphine, 5) Methadone, 6) Buprenorphine, 7) Tramadol);
  • Any pain diagnosis which may include, but not be limited to acute, chronic, mild, moderate, severe, neuropathic, nociceptive, mixed, post- operative, cancer related, superficial, visceral, treatment-refractory pain that may or may not be related to opioid use disorder (OUD), opioid-induced hyperalgesia (OIH), or opioid-induced tolerance (OIT).
  • OOD opioid use disorder
  • OIH opioid-induced hyperalgesia
  • OIT opioid-induced tolerance
  • Study Screening & Enrollment Individuals are screened and selected from a pool of a potential participants suffering chronic pain The participants are assigned to one of seven treatment subgroups that involve the co-administration of dronabinol and one of the following opioids: 1) Oxycodone, 2) Mixed Opioids, 3) Hydrocodone + Acetaminophen, 4) Morphine, 5) Methadone, 6) Buprenorphine, and 7) Tramadol.
  • opioids 1) Oxycodone, 2) Mixed Opioids, 3) Hydrocodone + Acetaminophen, 4) Morphine, 5) Methadone, 6) Buprenorphine, and 7) Tramadol.
  • Week one of the study is a Baseline Period during which time, baseline data related to opioid dose and frequency, mood, sleep, bowel movements, and pain intensity are collected. Participants receive no Dronabinol during week one and continue to take their stabilized dose of regular prescribed opioids, both baseline and rescue.
  • Weeks two through four are the Titration Period, during which time study participants titrate the dronabinol dose up to a daily dose of 20 mg of dronabinol per day, according to a prearranged titration table. Participants continue to take their stabilized dose of regular prescribed opioids, both baseline and rescue. Participants are encouraged to maintain the 20 mg daily total dose of dronabinol. Participants are permitted to reduce their dose of dronabinol at any time (if they experience severe adverse effects) to a minimum daily dose of dronabinol of 10 mg per day. Participants who are unable to tolerate at least a minimum daily dose of 10 mg of dronabinol per day are discontinued from the study.
  • Weeks five through twelve are the Opioid-Sparing Period, during which time participants are encouraged to maintain the stabilized dose of dronabinol that they“find” during the Study-Drug Dose Finding or Titration Period. Study Participants continue to take their regular prescribed opioids, but are encouraged to reduce their opioid dose and/or opioid dose frequency at any time during the remainder of the study should they experience a reduction in pain and/or an improvement in opioid-related side effects. Table 3

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Abstract

La présente invention concerne des associations pharmaceutiques comprenant un cannabinoïde, en particulier du dronabinol, et un opioïde, l'association pharmaceutique ayant une efficacité synergique. L'invention concerne également des méthodes de traitement ou de prévention de la douleur comprenant l'administration de l'association pharmaceutique.
PCT/US2018/063284 2017-12-12 2018-11-30 Procédés de renforcement et/ou d'économie d'opioïdes à partir d'associations co-administrées ou à dose fixe de dronabinol et d'un opioïde WO2019118205A1 (fr)

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WO2023278708A1 (fr) * 2021-07-01 2023-01-05 Ananda Scientific, Inc. Méthodes de traitement de la douleur au moyen de cannabinoïdes

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