{"history":[],"article":{"id":"73e64de1-0284-4132-8d9c-184e00a7daa6","title":"Nalbuphine","slug":"nalbuphine","content":":::summary\n:::\n\n# \n**Nalbuphine**, sold under the brand names **Nubain** among others, is an [opioid](https://bliptext.com/articles/opioid) [analgesic](https://bliptext.com/articles/analgesic) which is used in the treatment of [pain](https://bliptext.com/articles/pain).\nIt is given by [injection](https://bliptext.com/articles/injection-medicine) into a [vein](https://bliptext.com/articles/vein), [muscle](https://bliptext.com/articles/muscle), or [fat](https://bliptext.com/articles/fat).\n[Side effects](https://bliptext.com/articles/side-effect) of nalbuphine include [sedation](https://bliptext.com/articles/sedation), [sweatiness](https://bliptext.com/articles/sweatiness), [clamminess](https://bliptext.com/articles/clamminess), [nausea](https://bliptext.com/articles/nausea), [vomiting](https://bliptext.com/articles/vomiting), [dizziness](https://bliptext.com/articles/dizziness), [vertigo](https://bliptext.com/articles/vertigo), [dry mouth](https://bliptext.com/articles/dry-mouth), and [headache](https://bliptext.com/articles/headache).\nUnlike other opioids, it has little to no capacity to cause [euphoria](https://bliptext.com/articles/euphoria) or [respiratory depression](https://bliptext.com/articles/respiratory-depression).\nThere is also little to no incidence of [dysphoria](https://bliptext.com/articles/dysphoria), [dissociation](https://bliptext.com/articles/dissociative), [hallucinations](https://bliptext.com/articles/hallucination), and related side effects at typical therapeutic doses.\nNalbuphine is a [mixed agonist/antagonist](https://bliptext.com/articles/agonist-antagonist) [opioid modulator](https://bliptext.com/articles/opioid-modulator).\nSpecifically, it acts as a moderate-[efficacy](https://bliptext.com/articles/efficacy) [partial agonist](https://bliptext.com/articles/partial-agonist) or [antagonist](https://bliptext.com/articles/receptor-antagonist) of the [μ-opioid receptor](https://bliptext.com/articles/opioid-receptor) (MOR) and as a high-[efficacy](https://bliptext.com/articles/efficacy) [partial agonist](https://bliptext.com/articles/partial-agonist) of the [κ-opioid receptor](https://bliptext.com/articles/opioid-receptor) (KOR), whereas it has relatively low [affinity](https://bliptext.com/articles/affinity-pharmacology) for the [δ-opioid receptor](https://bliptext.com/articles/opioid-receptor) (DOR) and [sigma receptors](https://bliptext.com/articles/sigma-receptor).\nNalbuphine was patented in 1963 and was introduced for medical use in the [United States](https://bliptext.com/articles/united-states) in 1979.\nIt is marketed in many countries throughout the world.\n\n# Medical uses\nNalbuphine is indicated for the relief of moderate to severe pain.\nIt can also be used as a supplement to [balanced anesthesia](https://bliptext.com/articles/balanced-anesthesia), for preoperative and postoperative analgesia, and for obstetrical analgesia during labor and delivery.\nHowever, a [2014 Cochrane Systematic Review](https://bliptext.com/articles/10-1002-14651858-cd009583-pub2) concluded that from the included studies, there was limited evidence to demonstrate that \"0.1 to 0.3mg/kg nalbuphine compared to placebo might be an effective postoperative analgesic\" for pain treatment in children.\nFurther research is therefore needed to compare nalbuphine with other postoperative opioids.\nAlthough nalbuphine possesses opioid antagonist activity, there is evidence that in nondependent patients it will not antagonize an opioid analgesic administered just before, concurrently, or just after an injection.\nTherefore, patients receiving an opioid analgesic, general anesthetics, phenothiazines, or other tranquilizers, sedatives, hypnotics, or other CNS depressants (including [alcohol](https://bliptext.com/articles/alcohol-drug)) concomitantly with Nalbuphine may exhibit an additive effect.\nWhen such combined therapy is contemplated, the dose of one or both agents should be reduced.\nIn addition to the relief of pain, the drug has been studied as a treatment for morphine induced [pruritus](https://bliptext.com/articles/pruritus) (itching).\nPruritus is a common side effect of morphine or other pure MOR agonist opioid administration.\nKjellberg et al. (2001) published a review of clinical trials relating to the prevalence of morphine induced pruritus and its pharmacologic control.\nThe authors state that nalbuphine is an effective anti-pruritic agent against morphine induced pruritus.\nThe effect may be mediated via central nervous system mechanisms.\nPan (1998) summarizes the evidence that activation at the pharmacological level of the KOR antagonizes various MOR-mediated actions in the brain.\nThe author states that the neural mechanism for this potentially very general MOR-antagonizing function by the KOR may have broad applications in the treatment of central nervous system mediated diseases.\nHe does not state, however, that nalbuphine's pharmacological mechanism of action for pruritus is the result of this interaction between the two opioid receptors.\nMorphine induced pruritus syndrome may also be caused by release of histamine from [mast cells](https://bliptext.com/articles/mast-cell) in the skin (Gunion et al. (2004). Paus et al. (2006) report that MORs and KORs are located in skin nerves and keratinocytes. Levy et al. (1989) reviewed the literature on the relationship of opioid mediated histamine release from cutaneous [mast cells](https://bliptext.com/articles/mast-cell) to the etiology of hypotension, flushing and pruritus. The authors investigated the relative abilities of various opioids to induce histamine release mediated increased capillary permeability and tissue edema (\"wheal response\") and cutaneous vasodilatation and local redness (\"flare response\") when subjects were intradermally injected with 0.02 ml equimolar concentrations of 5 x 10-4 M. Nalbuphine did not produce either a wheal or flare response.\n\n## Available forms\nNalbuphine is available in two concentrations, 10 mg and 20 mg of nalbuphine hydrochloride per mL. Both strengths contain 0.94% sodium citrate hydrous, 1.26% citric acid anhydrous, 0.1% sodium metabisulfite, and 0.2% of a 9:1 mixture of methylparaben and propylparaben as preservatives; pH is adjusted, if necessary, with [hydrochloric acid](https://bliptext.com/articles/hydrochloric-acid).\nThe 10 mg/mL strength contains 0.1% sodium chloride.\nThe drug is also available in a [sulfite](https://bliptext.com/articles/sulfite) and paraben-free formulation in two concentrations, 10 mg and 20 mg of nalbuphine hydrochloride per mL. One mL of each strength contains 0.94% sodium citrate hydrous, 1.26% citric acid anhydrous; pH is adjusted, if necessary, with hydrochloric acid.\nThe 10 mg/mL strength contains 0.2% sodium chloride.\nAn investigational extended-release oral formulation is under development by Trevi Therapeutics.\n\n# Side effects\nLike pure MOR agonists, the mixed agonist/antagonist opioid class of drugs can cause side effects with initial administration of the drug which lessens over time (\"[tolerance](https://bliptext.com/articles/drug-tolerance)\").\nThis is particularly true for the side effects of nausea, sedation and cognitive symptoms (Jovey et al. 2003).\nThese side effects can in many instances be ameliorated or avoided at the time of drug initiation by titrating the drug from a tolerable starting dose up to the desired therapeutic dose.\nAn important difference between nalbuphine and the pure MOR agonist opioid analgesic drugs is the \"ceiling effect\" on respiration (but no ceiling on the analgesic effect).\nRespiratory depression is a potentially fatal side effect from the use of pure MOR agonists.\nNalbuphine has limited ability to depress respiratory function (Gal et al. 1982).\nAs reported in the current Nubain Package Insert (2005), the most frequent side effect in 1066 patients treated with nalbuphine was sedation in 381 (36%).\nOther, less frequent reactions are: feeling sweaty/clammy 99 (9%), nausea/vomiting 68 (6%), dizziness/vertigo 58 (5%), dry mouth 44 (4%), and headache 27 (3%).\nOther adverse reactions which may occur (reported incidence of 1% or less) are:\nOther possible, but rare side effects include speech difficulty, urinary urgency, blurred vision, flushing and warmth.\nA 2014 [Cochrane Systematic Review](https://bliptext.com/articles/10-1002-14651858-cd009583-pub2) by Schnabel et al., concluded that due to limited data, analysis of adverse events for children treated with nalbuphine compared to other opioids or placebo for postoperative pain, could not be definitively reported.\n\n# Overdose\nIn case of overdose or adverse reaction, the immediate intravenous administration of [naloxone](https://bliptext.com/articles/naloxone) (Narcan) is a specific antidote.\nOxygen, intravenous fluids, vasopressors and other supportive measures should be used as indicated.\n\n# Pharmacology\n\n## Pharmacodynamics\nNalbuphine is a [semisynthetic](https://bliptext.com/articles/semisynthetic) [mixed agonist/antagonist](https://bliptext.com/articles/agonist-antagonist) [opioid modulator](https://bliptext.com/articles/opioid-modulator) of the [phenanthrene](https://bliptext.com/articles/phenanthrene) or [morphinan](https://bliptext.com/articles/morphinan) series.\nIt is structurally related to the widely used [opioid antagonists](https://bliptext.com/articles/opioid-antagonist) [naloxone](https://bliptext.com/articles/naloxone) and [naltrexone](https://bliptext.com/articles/naltrexone), and to the potent opioid analgesic [oxymorphone](https://bliptext.com/articles/oxymorphone).\nNalbuphine binds with high [affinity](https://bliptext.com/articles/affinity-pharmacology) to the MOR and KOR, and has relatively low [affinity](https://bliptext.com/articles/affinity-pharmacology) for the DOR.\nIt behaves as a moderate-[efficacy](https://bliptext.com/articles/intrinsic-activity) [partial agonist](https://bliptext.com/articles/partial-agonist) (or mixed [agonist/antagonist](https://bliptext.com/articles/agonist-antagonist)) of the MOR and as a high-[efficacy](https://bliptext.com/articles/intrinsic-activity) [partial agonist](https://bliptext.com/articles/partial-agonist) of the KOR.\nNalbuphine has weak or no affinity for the [sigma receptor(s)](https://bliptext.com/articles/sigma-receptor) (e.g., Ki > 100,000 nM).\nNalbuphine is said to be more [morphine](https://bliptext.com/articles/morphine)-like at lower doses.\nHowever at higher doses, it produces more [sedation](https://bliptext.com/articles/sedation), [drunkenness](https://bliptext.com/articles/drunkenness), [dysphoria](https://bliptext.com/articles/dysphoria), and [dissociation](https://bliptext.com/articles/dissociative).\nAs such, its effects are [dose-dependent](https://bliptext.com/articles/dose-response-relationship).\nSuch effects include sedation (21–36%), [dizziness](https://bliptext.com/articles/dizziness) or [vertigo](https://bliptext.com/articles/vertigo) (5%), [lightheadedness](https://bliptext.com/articles/lightheadedness) (1%), [anxiety](https://bliptext.com/articles/anxiety) (<1%), dysphoria (<1%), [euphoria](https://bliptext.com/articles/euphoria) (<1%), [confusion](https://bliptext.com/articles/mental-confusion) (<1%), [hallucinations](https://bliptext.com/articles/hallucination) (<1%), [depersonalization](https://bliptext.com/articles/depersonalization) (1%), unusual [dreams](https://bliptext.com/articles/dream) (<1%), and [feelings of \"unreality\"](https://bliptext.com/articles/derealization) (<1%).\nNalbuphine is a potent analgesic.\nIts analgesic potency is essentially equivalent to that of morphine on a milligram basis, which is based on relative potency studies using intramuscular administration (Beaver et al. 1978).\nOral administered nalbuphine is reported to be three times more potent than codeine (Okun et al. 1982).\nClinical trials studied single dose experimental oral immediate release nalbuphine tablets for analgesic efficacy over a four- to six-hour time period following administration.\nNalbuphine in the 15 to 60 mg range had similar analgesic effects to immediate release codeine in the 30 to 60 mg range (Kantor et al. 1984; Sunshine et al. 1983).\nSchmidt et al. (1985) reviewed the preclinical pharmacology of nalbuphine and reported comparative data relative to other types of opioid compounds.\nThe authors point out that the nalbuphine [moiety](https://bliptext.com/articles/moiety-chemistry) is approximately ten times more pharmacologically potent than the mixed opioid agonist/antagonist [butorphanol](https://bliptext.com/articles/butorphanol) on an \"antagonist index\" scale which quantitates the drug's ability to act both as an analgesic (via opioid KOR agonism) as well as a MOR antagonist.\nThe opioid antagonist activity of nalbuphine is one-fourth as potent as [nalorphine](https://bliptext.com/articles/nalorphine) and 10 times that of [pentazocine](https://bliptext.com/articles/pentazocine).\n\n## Pharmacokinetics\nThe [onset of action](https://bliptext.com/articles/onset-of-action) of nalbuphine occurs within 2 to 3 minutes after [intravenous administration](https://bliptext.com/articles/intravenous-administration), and in less than 15 minutes following [subcutaneous](https://bliptext.com/articles/subcutaneous-injection) or [intramuscular injection](https://bliptext.com/articles/intramuscular-injection).\nThe [elimination half-life](https://bliptext.com/articles/elimination-half-life) of nalbuphine is approximately 5 hours on average and in clinical studies the [duration](https://bliptext.com/articles/duration-of-action) of analgesic activity has been reported to range from 3 to 6 hours.\n\n# Chemistry\nNalbuphine is a [derivative](https://bliptext.com/articles/chemical-derivative) of [morphine](https://bliptext.com/articles/morphine) and is also known as N-cyclobutylmethyl-14-hydroxydihydronor[morphine](https://bliptext.com/articles/morphine).\n\n# History\nNalbuphine was first [synthesized](https://bliptext.com/articles/chemical-synthesis) in 1965 and was introduced for medical use in the [United States](https://bliptext.com/articles/united-states) in 1979.\nIn the search for opioid analgesics with less abuse potential than pure MOR agonist opioids, a number of [semisynthetic opioids](https://bliptext.com/articles/semisynthetic-opioid) were developed.\nThese substances are referred to as mixed [agonist–antagonists](https://bliptext.com/articles/agonist-antagonist) analgesics.\nNalbuphine belongs to this group of substances.\nThe mixed agonists-antagonists drug class exerts their analgesic actions by agonistic activity at the KOR.\nWhile all drugs in this class possess MOR antagonistic activity leading to less abuse potential, nalbuphine is the only approved drug in the mixed agonist–antagonist class listed in terms of its pharmacological actions and selectivities on opioid receptors as a MOR partial agonist or antagonist as well as a KOR agonist (Gustein et al. 2001).\nNubain was approved for marketing in the United States in 1978 and remains as the only opioid analgesic of this type (marketed in the U.S.) not controlled under the [Controlled Substances Act](https://bliptext.com/articles/controlled-substances-act) (CSA).\nWhen the Controlled Substances Act (CSA) was enacted in 1971, nalbuphine was placed in [schedule II](https://bliptext.com/articles/controlled-substances-act).\nEndo Laboratories, Inc. subsequently petitioned the DEA to exclude nalbuphine from all schedules of the CSA in 1973.\nAfter receiving a medical and scientific review and a scheduling recommendation from the Department of Health, Education and Welfare, forerunner to the [Department of Health and Human Services](https://bliptext.com/articles/department-of-health-and-human-services), nalbuphine was removed from schedule II of the CSA in 1976.\nPresently, nalbuphine is not a controlled substance under the CSA.\nNalbuphine HCL is currently available only as an injectable in the US and the [European Union](https://bliptext.com/articles/european-union).\nNubain, the Astra USA brand name for injectable nalbuphine HCL, was discontinued from being marketed in 2008 in the United States for commercial reasons (Federal Register 2008); however, other commercial suppliers now provide generic injection formulation nalbuphine for the market.\n\n# Society and culture\n\n## Brand names\nNalbuphine is marketed primarily under the brand names Nubain, Nalpain, and Nalbuphin.\nIt is also marketed under the brand name Nalufin in [Egypt](https://bliptext.com/articles/egypt) and Raltrox in [Bangladesh](https://bliptext.com/articles/bangladesh) by Opsonin Pharma Limited, under the brand name Rubuphine in [India](https://bliptext.com/articles/india) by Rusan Healthcare Pvt Ltd, under the brand name Kinz and Nalbin in [Pakistan](https://bliptext.com/articles/pakistan) by Sami and Global Pharmaceuticals, under the brand name Analin by Medicaids in [Pakistan](https://bliptext.com/articles/pakistan), and under the brand name Exnal by Indus Pharma in [Pakistan](https://bliptext.com/articles/pakistan), among many others.\n\n## Legal status\nUnlike many other opioids, nalbuphine has a limited potential for [euphoria](https://bliptext.com/articles/euphoria), and in accordance, is rarely abused.\nThis is because whereas MOR agonists produce euphoria, MOR antagonists do not, and KOR agonists like nalbuphine moreover actually produce [dysphoria](https://bliptext.com/articles/dysphoria).\nNalbuphine was initially designated as a [Schedule II](https://bliptext.com/articles/controlled-substances-act) [controlled substance](https://bliptext.com/articles/controlled-substance) in the [United States](https://bliptext.com/articles/united-states) along with other opioids upon the introduction of the 1970 [Controlled Substances Act](https://bliptext.com/articles/controlled-substances-act).\nHowever, its manufacturer, Endo Laboratories, Inc., petitioned the [Food and Drug Administration](https://bliptext.com/articles/food-and-drug-administration) to remove it from Schedule II in 1973, and after a medical and scientific review, nalbuphine was removed completely from the Controlled Substances Act in 1976 and is not a controlled substance in the United States today.\nFor comparison, MOR full agonists are all Schedule II in the United States, whereas the mixed KOR and MOR agonists/antagonists [butorphanol](https://bliptext.com/articles/butorphanol) and [pentazocine](https://bliptext.com/articles/pentazocine) are Schedule IV in the United States.\nIn [Canada](https://bliptext.com/articles/canada), most opioids are classified as [Schedule I](https://bliptext.com/articles/controlled-drugs-and-substances-act), but nalbuphine and butorphanol are both listed as [Schedule I](https://bliptext.com/articles/controlled-drugs-and-substances-act)V substances.","current_revision":null,"created_by":"kACnuQmH5k9Nr5VNVEpVeg7XpvUmMctD","created_at":"2025-01-25T21:58:52.551Z","updated_at":"2025-01-25T21:58:52.551Z","search_vector":"'nalbuphin':1","search_content":" \n \n\n# \n**Nalbuphine**, sold under the brand names **Nubain** among others, is an [opioid](https://bliptext.com/articles/opioid) [analgesic](https://bliptext.com/articles/analgesic) which is used in the treatment of [pain](https://bliptext.com/articles/pain).\nIt is given by [injection](https://bliptext.com/articles/injection-medicine) into a [vein](https://bliptext.com/articles/vein), [muscle](https://bliptext.com/articles/muscle), or [fat](https://bliptext.com/articles/fat).\n[Side effects](https://bliptext.com/articles/side-effect) of nalbuphine include [sedation](https://bliptext.com/articles/sedation), [sweatiness](https://bliptext.com/articles/sweatiness), [clamminess](https://bliptext.com/articles/clamminess), [nausea](https://bliptext.com/articles/nausea), [vomiting](https://bliptext.com/articles/vomiting), [dizziness](https://bliptext.com/articles/dizziness), [vertigo](https://bliptext.com/articles/vertigo), [dry mouth](https://bliptext.com/articles/dry-mouth), and [headache](https://bliptext.com/articles/headache).\nUnlike other opioids, it has little to no capacity to cause [euphoria](https://bliptext.com/articles/euphoria) or [respiratory depression](https://bliptext.com/articles/respiratory-depression).\nThere is also little to no incidence of [dysphoria](https://bliptext.com/articles/dysphoria), [dissociation](https://bliptext.com/articles/dissociative), [hallucinations](https://bliptext.com/articles/hallucination), and related side effects at typical therapeutic doses.\nNalbuphine is a [mixed agonist/antagonist](https://bliptext.com/articles/agonist-antagonist) [opioid modulator](https://bliptext.com/articles/opioid-modulator).\nSpecifically, it acts as a moderate-[efficacy](https://bliptext.com/articles/efficacy) [partial agonist](https://bliptext.com/articles/partial-agonist) or [antagonist](https://bliptext.com/articles/receptor-antagonist) of the [μ-opioid receptor](https://bliptext.com/articles/opioid-receptor) (MOR) and as a high-[efficacy](https://bliptext.com/articles/efficacy) [partial agonist](https://bliptext.com/articles/partial-agonist) of the [κ-opioid receptor](https://bliptext.com/articles/opioid-receptor) (KOR), whereas it has relatively low [affinity](https://bliptext.com/articles/affinity-pharmacology) for the [δ-opioid receptor](https://bliptext.com/articles/opioid-receptor) (DOR) and [sigma receptors](https://bliptext.com/articles/sigma-receptor).\nNalbuphine was patented in 1963 and was introduced for medical use in the [United States](https://bliptext.com/articles/united-states) in 1979.\nIt is marketed in many countries throughout the world.\n\n# Medical uses\nNalbuphine is indicated for the relief of moderate to severe pain.\nIt can also be used as a supplement to [balanced anesthesia](https://bliptext.com/articles/balanced-anesthesia), for preoperative and postoperative analgesia, and for obstetrical analgesia during labor and delivery.\nHowever, a [2014 Cochrane Systematic Review](https://bliptext.com/articles/10-1002-14651858-cd009583-pub2) concluded that from the included studies, there was limited evidence to demonstrate that \"0.1 to 0.3mg/kg nalbuphine compared to placebo might be an effective postoperative analgesic\" for pain treatment in children.\nFurther research is therefore needed to compare nalbuphine with other postoperative opioids.\nAlthough nalbuphine possesses opioid antagonist activity, there is evidence that in nondependent patients it will not antagonize an opioid analgesic administered just before, concurrently, or just after an injection.\nTherefore, patients receiving an opioid analgesic, general anesthetics, phenothiazines, or other tranquilizers, sedatives, hypnotics, or other CNS depressants (including [alcohol](https://bliptext.com/articles/alcohol-drug)) concomitantly with Nalbuphine may exhibit an additive effect.\nWhen such combined therapy is contemplated, the dose of one or both agents should be reduced.\nIn addition to the relief of pain, the drug has been studied as a treatment for morphine induced [pruritus](https://bliptext.com/articles/pruritus) (itching).\nPruritus is a common side effect of morphine or other pure MOR agonist opioid administration.\nKjellberg et al. (2001) published a review of clinical trials relating to the prevalence of morphine induced pruritus and its pharmacologic control.\nThe authors state that nalbuphine is an effective anti-pruritic agent against morphine induced pruritus.\nThe effect may be mediated via central nervous system mechanisms.\nPan (1998) summarizes the evidence that activation at the pharmacological level of the KOR antagonizes various MOR-mediated actions in the brain.\nThe author states that the neural mechanism for this potentially very general MOR-antagonizing function by the KOR may have broad applications in the treatment of central nervous system mediated diseases.\nHe does not state, however, that nalbuphine's pharmacological mechanism of action for pruritus is the result of this interaction between the two opioid receptors.\nMorphine induced pruritus syndrome may also be caused by release of histamine from [mast cells](https://bliptext.com/articles/mast-cell) in the skin (Gunion et al. (2004). Paus et al. (2006) report that MORs and KORs are located in skin nerves and keratinocytes. Levy et al. (1989) reviewed the literature on the relationship of opioid mediated histamine release from cutaneous [mast cells](https://bliptext.com/articles/mast-cell) to the etiology of hypotension, flushing and pruritus. The authors investigated the relative abilities of various opioids to induce histamine release mediated increased capillary permeability and tissue edema (\"wheal response\") and cutaneous vasodilatation and local redness (\"flare response\") when subjects were intradermally injected with 0.02 ml equimolar concentrations of 5 x 10-4 M. Nalbuphine did not produce either a wheal or flare response.\n\n## Available forms\nNalbuphine is available in two concentrations, 10 mg and 20 mg of nalbuphine hydrochloride per mL. Both strengths contain 0.94% sodium citrate hydrous, 1.26% citric acid anhydrous, 0.1% sodium metabisulfite, and 0.2% of a 9:1 mixture of methylparaben and propylparaben as preservatives; pH is adjusted, if necessary, with [hydrochloric acid](https://bliptext.com/articles/hydrochloric-acid).\nThe 10 mg/mL strength contains 0.1% sodium chloride.\nThe drug is also available in a [sulfite](https://bliptext.com/articles/sulfite) and paraben-free formulation in two concentrations, 10 mg and 20 mg of nalbuphine hydrochloride per mL. One mL of each strength contains 0.94% sodium citrate hydrous, 1.26% citric acid anhydrous; pH is adjusted, if necessary, with hydrochloric acid.\nThe 10 mg/mL strength contains 0.2% sodium chloride.\nAn investigational extended-release oral formulation is under development by Trevi Therapeutics.\n\n# Side effects\nLike pure MOR agonists, the mixed agonist/antagonist opioid class of drugs can cause side effects with initial administration of the drug which lessens over time (\"[tolerance](https://bliptext.com/articles/drug-tolerance)\").\nThis is particularly true for the side effects of nausea, sedation and cognitive symptoms (Jovey et al. 2003).\nThese side effects can in many instances be ameliorated or avoided at the time of drug initiation by titrating the drug from a tolerable starting dose up to the desired therapeutic dose.\nAn important difference between nalbuphine and the pure MOR agonist opioid analgesic drugs is the \"ceiling effect\" on respiration (but no ceiling on the analgesic effect).\nRespiratory depression is a potentially fatal side effect from the use of pure MOR agonists.\nNalbuphine has limited ability to depress respiratory function (Gal et al. 1982).\nAs reported in the current Nubain Package Insert (2005), the most frequent side effect in 1066 patients treated with nalbuphine was sedation in 381 (36%).\nOther, less frequent reactions are: feeling sweaty/clammy 99 (9%), nausea/vomiting 68 (6%), dizziness/vertigo 58 (5%), dry mouth 44 (4%), and headache 27 (3%).\nOther adverse reactions which may occur (reported incidence of 1% or less) are:\nOther possible, but rare side effects include speech difficulty, urinary urgency, blurred vision, flushing and warmth.\nA 2014 [Cochrane Systematic Review](https://bliptext.com/articles/10-1002-14651858-cd009583-pub2) by Schnabel et al., concluded that due to limited data, analysis of adverse events for children treated with nalbuphine compared to other opioids or placebo for postoperative pain, could not be definitively reported.\n\n# Overdose\nIn case of overdose or adverse reaction, the immediate intravenous administration of [naloxone](https://bliptext.com/articles/naloxone) (Narcan) is a specific antidote.\nOxygen, intravenous fluids, vasopressors and other supportive measures should be used as indicated.\n\n# Pharmacology\n\n## Pharmacodynamics\nNalbuphine is a [semisynthetic](https://bliptext.com/articles/semisynthetic) [mixed agonist/antagonist](https://bliptext.com/articles/agonist-antagonist) [opioid modulator](https://bliptext.com/articles/opioid-modulator) of the [phenanthrene](https://bliptext.com/articles/phenanthrene) or [morphinan](https://bliptext.com/articles/morphinan) series.\nIt is structurally related to the widely used [opioid antagonists](https://bliptext.com/articles/opioid-antagonist) [naloxone](https://bliptext.com/articles/naloxone) and [naltrexone](https://bliptext.com/articles/naltrexone), and to the potent opioid analgesic [oxymorphone](https://bliptext.com/articles/oxymorphone).\nNalbuphine binds with high [affinity](https://bliptext.com/articles/affinity-pharmacology) to the MOR and KOR, and has relatively low [affinity](https://bliptext.com/articles/affinity-pharmacology) for the DOR.\nIt behaves as a moderate-[efficacy](https://bliptext.com/articles/intrinsic-activity) [partial agonist](https://bliptext.com/articles/partial-agonist) (or mixed [agonist/antagonist](https://bliptext.com/articles/agonist-antagonist)) of the MOR and as a high-[efficacy](https://bliptext.com/articles/intrinsic-activity) [partial agonist](https://bliptext.com/articles/partial-agonist) of the KOR.\nNalbuphine has weak or no affinity for the [sigma receptor(s)](https://bliptext.com/articles/sigma-receptor) (e.g., Ki > 100,000 nM).\nNalbuphine is said to be more [morphine](https://bliptext.com/articles/morphine)-like at lower doses.\nHowever at higher doses, it produces more [sedation](https://bliptext.com/articles/sedation), [drunkenness](https://bliptext.com/articles/drunkenness), [dysphoria](https://bliptext.com/articles/dysphoria), and [dissociation](https://bliptext.com/articles/dissociative).\nAs such, its effects are [dose-dependent](https://bliptext.com/articles/dose-response-relationship).\nSuch effects include sedation (21–36%), [dizziness](https://bliptext.com/articles/dizziness) or [vertigo](https://bliptext.com/articles/vertigo) (5%), [lightheadedness](https://bliptext.com/articles/lightheadedness) (1%), [anxiety](https://bliptext.com/articles/anxiety) (<1%), dysphoria (<1%), [euphoria](https://bliptext.com/articles/euphoria) (<1%), [confusion](https://bliptext.com/articles/mental-confusion) (<1%), [hallucinations](https://bliptext.com/articles/hallucination) (<1%), [depersonalization](https://bliptext.com/articles/depersonalization) (1%), unusual [dreams](https://bliptext.com/articles/dream) (<1%), and [feelings of \"unreality\"](https://bliptext.com/articles/derealization) (<1%).\nNalbuphine is a potent analgesic.\nIts analgesic potency is essentially equivalent to that of morphine on a milligram basis, which is based on relative potency studies using intramuscular administration (Beaver et al. 1978).\nOral administered nalbuphine is reported to be three times more potent than codeine (Okun et al. 1982).\nClinical trials studied single dose experimental oral immediate release nalbuphine tablets for analgesic efficacy over a four- to six-hour time period following administration.\nNalbuphine in the 15 to 60 mg range had similar analgesic effects to immediate release codeine in the 30 to 60 mg range (Kantor et al. 1984; Sunshine et al. 1983).\nSchmidt et al. (1985) reviewed the preclinical pharmacology of nalbuphine and reported comparative data relative to other types of opioid compounds.\nThe authors point out that the nalbuphine [moiety](https://bliptext.com/articles/moiety-chemistry) is approximately ten times more pharmacologically potent than the mixed opioid agonist/antagonist [butorphanol](https://bliptext.com/articles/butorphanol) on an \"antagonist index\" scale which quantitates the drug's ability to act both as an analgesic (via opioid KOR agonism) as well as a MOR antagonist.\nThe opioid antagonist activity of nalbuphine is one-fourth as potent as [nalorphine](https://bliptext.com/articles/nalorphine) and 10 times that of [pentazocine](https://bliptext.com/articles/pentazocine).\n\n## Pharmacokinetics\nThe [onset of action](https://bliptext.com/articles/onset-of-action) of nalbuphine occurs within 2 to 3 minutes after [intravenous administration](https://bliptext.com/articles/intravenous-administration), and in less than 15 minutes following [subcutaneous](https://bliptext.com/articles/subcutaneous-injection) or [intramuscular injection](https://bliptext.com/articles/intramuscular-injection).\nThe [elimination half-life](https://bliptext.com/articles/elimination-half-life) of nalbuphine is approximately 5 hours on average and in clinical studies the [duration](https://bliptext.com/articles/duration-of-action) of analgesic activity has been reported to range from 3 to 6 hours.\n\n# Chemistry\nNalbuphine is a [derivative](https://bliptext.com/articles/chemical-derivative) of [morphine](https://bliptext.com/articles/morphine) and is also known as N-cyclobutylmethyl-14-hydroxydihydronor[morphine](https://bliptext.com/articles/morphine).\n\n# History\nNalbuphine was first [synthesized](https://bliptext.com/articles/chemical-synthesis) in 1965 and was introduced for medical use in the [United States](https://bliptext.com/articles/united-states) in 1979.\nIn the search for opioid analgesics with less abuse potential than pure MOR agonist opioids, a number of [semisynthetic opioids](https://bliptext.com/articles/semisynthetic-opioid) were developed.\nThese substances are referred to as mixed [agonist–antagonists](https://bliptext.com/articles/agonist-antagonist) analgesics.\nNalbuphine belongs to this group of substances.\nThe mixed agonists-antagonists drug class exerts their analgesic actions by agonistic activity at the KOR.\nWhile all drugs in this class possess MOR antagonistic activity leading to less abuse potential, nalbuphine is the only approved drug in the mixed agonist–antagonist class listed in terms of its pharmacological actions and selectivities on opioid receptors as a MOR partial agonist or antagonist as well as a KOR agonist (Gustein et al. 2001).\nNubain was approved for marketing in the United States in 1978 and remains as the only opioid analgesic of this type (marketed in the U.S.) not controlled under the [Controlled Substances Act](https://bliptext.com/articles/controlled-substances-act) (CSA).\nWhen the Controlled Substances Act (CSA) was enacted in 1971, nalbuphine was placed in [schedule II](https://bliptext.com/articles/controlled-substances-act).\nEndo Laboratories, Inc. subsequently petitioned the DEA to exclude nalbuphine from all schedules of the CSA in 1973.\nAfter receiving a medical and scientific review and a scheduling recommendation from the Department of Health, Education and Welfare, forerunner to the [Department of Health and Human Services](https://bliptext.com/articles/department-of-health-and-human-services), nalbuphine was removed from schedule II of the CSA in 1976.\nPresently, nalbuphine is not a controlled substance under the CSA.\nNalbuphine HCL is currently available only as an injectable in the US and the [European Union](https://bliptext.com/articles/european-union).\nNubain, the Astra USA brand name for injectable nalbuphine HCL, was discontinued from being marketed in 2008 in the United States for commercial reasons (Federal Register 2008); however, other commercial suppliers now provide generic injection formulation nalbuphine for the market.\n\n# Society and culture\n\n## Brand names\nNalbuphine is marketed primarily under the brand names Nubain, Nalpain, and Nalbuphin.\nIt is also marketed under the brand name Nalufin in [Egypt](https://bliptext.com/articles/egypt) and Raltrox in [Bangladesh](https://bliptext.com/articles/bangladesh) by Opsonin Pharma Limited, under the brand name Rubuphine in [India](https://bliptext.com/articles/india) by Rusan Healthcare Pvt Ltd, under the brand name Kinz and Nalbin in [Pakistan](https://bliptext.com/articles/pakistan) by Sami and Global Pharmaceuticals, under the brand name Analin by Medicaids in [Pakistan](https://bliptext.com/articles/pakistan), and under the brand name Exnal by Indus Pharma in [Pakistan](https://bliptext.com/articles/pakistan), among many others.\n\n## Legal status\nUnlike many other opioids, nalbuphine has a limited potential for [euphoria](https://bliptext.com/articles/euphoria), and in accordance, is rarely abused.\nThis is because whereas MOR agonists produce euphoria, MOR antagonists do not, and KOR agonists like nalbuphine moreover actually produce [dysphoria](https://bliptext.com/articles/dysphoria).\nNalbuphine was initially designated as a [Schedule II](https://bliptext.com/articles/controlled-substances-act) [controlled substance](https://bliptext.com/articles/controlled-substance) in the [United States](https://bliptext.com/articles/united-states) along with other opioids upon the introduction of the 1970 [Controlled Substances Act](https://bliptext.com/articles/controlled-substances-act).\nHowever, its manufacturer, Endo Laboratories, Inc., petitioned the [Food and Drug Administration](https://bliptext.com/articles/food-and-drug-administration) to remove it from Schedule II in 1973, and after a medical and scientific review, nalbuphine was removed completely from the Controlled Substances Act in 1976 and is not a controlled substance in the United States today.\nFor comparison, MOR full agonists are all Schedule II in the United States, whereas the mixed KOR and MOR agonists/antagonists [butorphanol](https://bliptext.com/articles/butorphanol) and [pentazocine](https://bliptext.com/articles/pentazocine) are Schedule IV in the United States.\nIn [Canada](https://bliptext.com/articles/canada), most opioids are classified as [Schedule I](https://bliptext.com/articles/controlled-drugs-and-substances-act), but nalbuphine and butorphanol are both listed as [Schedule I](https://bliptext.com/articles/controlled-drugs-and-substances-act)V substances.","revisionCount":0},"hasMore":false,"nextCursor":null}