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| Trade names | Nubain, Nalpain, Nalbuphin, others |
| Other names | EN-2234A;N-Cyclobutylmethyl-14-hydroxydihydronormorphine; 17-Cyclobutylmethyl-4,5α-epoxymorphinan-3,6α,14-triol;N-Cyclobutylmethyl-4,5α-epoxy-3,6α,14-morphinantriol |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a682668 |
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| Routes of administration | Intravenous,intramuscular,subcutaneous |
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| Bioavailability | •Oral: 11% (young adults), >44% (elderly)[4] •IMTooltip Intramuscular injection: 81% (10 mg), 83% (20 mg) •SCTooltip Subcutaneous injection: 76% (20 mg), 79% (10 mg)[5] |
| Protein binding | 50%[4] |
| Metabolism | Liver (glucuronidation)[7][4] |
| Metabolites | Glucuronideconjugates (inactive), others[6][7][4] |
| Onset of action | •Oral: <1 hour[4] •Rectal: <30 minutes[4] •IVTooltip Intravenous injection: 2–3 minutes[8] •IMTooltip Intramuscular injection: <15 minutes[8] •SCTooltip Subcutaneous injection: <15 minutes[8] |
| Eliminationhalf-life | ~5 hours (3–6 hours)<[6] |
| Duration of action | 3–6 hours[8] |
| Excretion | Urine,bile,feces;[4] 93% within 6 hours[9] |
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| ECHA InfoCard | 100.039.895 |
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| Formula | C21H27NO4 |
| Molar mass | 357.450 g·mol−1 |
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Nalbuphine, sold under the brand namesNubain among others, is anopioidanalgesic which is used in the treatment ofpain.[6][10][8] It is given byinjection into avein,muscle, orfat.[6][8]
Side effects of nalbuphine includesedation,sweatiness,clamminess,nausea,vomiting,dizziness,vertigo,dry mouth, andheadache.[10] Unlike other opioids, it has little to no capacity to causeeuphoria orrespiratory depression.[6][10] There is also little to no incidence ofdysphoria,dissociation,hallucinations, and related side effects at typical therapeutic doses.[6][10] Nalbuphine is amixed agonist/antagonistopioid modulator.[6][10] Specifically, it acts as a moderate-efficacypartial agonist orantagonist of theμ-opioid receptor (MOR) and as a high-efficacy partial agonist of theκ-opioid receptor (KOR), whereas it has relatively lowaffinity for theδ-opioid receptor (DOR) andsigma receptors.[11][10]
Nalbuphine was patented in 1968[12] and was introduced for medical use in theUnited States in 1979.[13][14] It is marketed in many countries throughout the world.[15]
Nalbuphine is indicated for the relief of moderate to severe pain. It can also be used as a supplement tobalanced anesthesia, for preoperative and postoperative analgesia, and for obstetrical analgesia during labor and delivery. However, a2014 Cochrane Systematic Review concluded that from the included studies, there was limited evidence to demonstrate that "0.1 to 0.3 mg/kg nalbuphine compared to placebo might be an effective postoperative analgesic" for pain treatment in children.[16] Further research is therefore needed to compare nalbuphine with other postoperative opioids.[16]
In addition to relieving pain, nalbuphine has been shown to reduce morphine-inducedpruritus (itching).[17] Pruritus is a common side effect of morphine and other pure μ-opioid receptor (MOR) agonists. A systematic review of clinical trials concluded that nalbuphine is effective in counteracting morphine-induced pruritus, likely through central nervous system mechanisms.[18]
Evidence suggests that κ-opioid receptor (KOR) activation can counteract MOR-mediated effects in the brain.[19] This interaction may have broader implications for central nervous system disorders, including potential applications in treatingParkinson's disease, where KOR agonism and MOR antagonism have been shown to reduce levodopa-induced dyskinesia and normalize striatal function.[20]
Morphine-induced pruritus may also result from histamine release bymast cells in the skin.[21] Both MORs and KORs are expressed in skin nerves and keratinocytes, indicating potential peripheral mechanisms for opioid-induced pruritus.[22] Histamine-mediated responses such as increased capillary permeability and vasodilation have been observed following intradermal administration of some opioids. However, nalbuphine does not elicit either a wheal or flare response, suggesting it does not promote histamine release from mast cells.[23]
Nalbuphine 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, withhydrochloric acid. The 10 mg/mL strength contains 0.1% sodium chloride. The drug is also available in asulfite 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. The 10 mg/mL strength contains 0.2% sodium chloride.[citation needed]
An investigational extended-release oral formulation is under development by Trevi Therapeutics.[24][independent source needed]
A 2014Cochrane Systematic Review 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.[16]
In case of overdose or adverse reaction, the immediate intravenous administration ofnaloxone (Narcan) is a specific antidote. Oxygen, intravenous fluids, vasopressors and other supportive measures should be used as indicated.[25] When administered concurrently with naloxone, nalbuphine is also useful for treating overdoses of potent opioids such asfentanyl, and its highly potent derivatives such asremifentanil andsufentanil, when naloxone alone is insufficient.[26]
| Site | KiTooltip Inhibitor constant | EC50Tooltip Half-maximal effective concentration | IATooltip Intrinsic activity | Ref |
|---|---|---|---|---|
| MORTooltip μ-Opioid receptor | 0.89 nM | 14 nM | 47% | [11] |
| DORTooltip δ-Opioid receptor | 240 nM | ND | ND | [11] |
| KORTooltip κ-Opioid receptor | 2.2 nM | 27 nM | 81% | [11] |
Nalbuphine is asemisyntheticmixed agonist/antagonistopioid modulator of thephenanthrene ormorphinan series. It is structurally related to the widely usedopioid antagonistsnaloxone andnaltrexone, and to the potent opioid analgesicoxymorphone. Nalbuphine binds with highaffinity to the MOR and KOR,[11] and has relatively low affinity for the DOR.[11] It behaves as a moderate-efficacypartial agonist (or mixedagonist/antagonist) of the MOR and as a high-efficacy partial agonist of the KOR.[11] Nalbuphine has weak or no affinity for thesigma receptor(s) (e.g., Ki > 100,000 nM).[10][27][28]
Nalbuphine is said to be moremorphine-like at lower doses. However at higher doses, it produces moresedation,drunkenness,dysphoria, anddissociation.[29] As such, its effects aredose-dependent.[30] Such effects include sedation (21–36%),dizziness orvertigo (5%),lightheadedness (1%),anxiety (<1%), dysphoria (<1%),euphoria (<1%),confusion (<1%),hallucinations (<1%),depersonalization (1%), unusualdreams (<1%), andfeelings of "unreality" (<1%).[30]
Nalbuphine is a potent analgesic. Its 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). Oral administered nalbuphine is reported to be three times more potent than codeine (Okun et al. 1982). Clinical trials studied single dose experimental oral immediate release nalbuphine tablets for analgesic efficacy over a four- to six-hour time period following administration. Nalbuphine 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). Schmidt et al. (1985) reviewed the preclinical pharmacology of nalbuphine and reported comparative data relative to other types of opioid compounds. The authors point out that the nalbuphinemoiety is approximately ten times more pharmacologically potent than the mixed opioid agonist/antagonistbutorphanol 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. The opioid antagonist activity of nalbuphine is one-fourth as potent asnalorphine and 10 times that ofpentazocine.[citation needed]
Nalbuphine is aderivative ofmorphine and is also known asN-cyclobutylmethyl-14-hydroxydihydronormorphine.[citation needed]
Nalbuphine was firstsynthesized in 1965 and was introduced for medical use in theUnited States in 1979.[14]
In the search for opioid analgesics with less abuse potential than pure MOR agonist opioids, a number ofsemisynthetic opioids were developed. These substances are referred to as mixedagonist–antagonists analgesics. Nalbuphine belongs to this group of substances. The mixed agonists-antagonists drug class exerts their analgesic actions by agonistic activity at the KOR. While 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).[full citation needed]
Nubain 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 theControlled Substances Act (CSA). When the Controlled Substances Act (CSA) was enacted in 1971, nalbuphine was placed inschedule II. Endo Laboratories, Inc. subsequently petitioned the DEA to exclude nalbuphine from all schedules of the CSA in 1973. After receiving a medical and scientific review and a scheduling recommendation from the Department of Health, Education and Welfare, forerunner to theDepartment of Health and Human Services, nalbuphine was removed from schedule II of the CSA in 1976. Presently, nalbuphine is not a controlled substance under the CSA.[citation needed]
Nalbuphine HCL is currently available only as an injectable in the US and theEuropean Union. Nubain, 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.[citation needed]
Nalbuphine is marketed primarily under the brand names Nubain, Nalpain, and Nalbuphin.[15] It is also marketed under the brand name Nalufin inEgypt and Raltrox inBangladesh by Opsonin Pharma Limited, under the brand name Rubuphine inIndia by Rusan Healthcare Pvt Ltd, under the brand name Kinz and Nalbin inPakistan by Sami and Global Pharmaceuticals, under the brand name Analin by Medicaids in Pakistan, and under the brand name Exnal by Indus Pharma in Pakistan, among many others.[15]
Unlike many other opioids, nalbuphine has a limited potential foreuphoria, and in accordance, is rarely abused.[6][30] This is because whereas MOR agonists produce euphoria, MOR antagonists do not, and KOR agonists like nalbuphine moreover actually producedysphoria.[6][29] Nalbuphine was initially designated as aSchedule IIcontrolled substance in theUnited States along with other opioids upon the introduction of the 1970Controlled Substances Act.[6] However, its manufacturer, Endo Laboratories, Inc., petitioned theFood 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.[6][29] For comparison, MOR full agonists are all Schedule II in the United States, whereas the mixed KOR and MOR agonists/antagonistsbutorphanol andpentazocine are Schedule IV in the United States.[29] InCanada, most opioids are classified asSchedule I, but nalbuphine and butorphanol are both listed asSchedule IV substances.[31]
There is limited data on nalbuphine's use in the dog, and even less for that of other animals. Nalbuphine induces sedation and analgesia in the dog but is less effective compared to μ-opioid receptor agonists. Nalbuphine has minimal effect on the cardiovascular system.[32] The sedation provided by nalbuphine is insufficient for catheterisation and fur clipping and the analgesic effect is insufficient for some pain.[33][32] Both sedative and analgesic effects of nalbuphine are subject to aceiling effect. Combination of nalbuphine with an α2-adrenergic receptor agonist oracepromazine provides greater sedation.[32] One study found that acepromazine and nalbuphine failed to provide adequate analgesia both during and post-surgery in bitches undergoing ovariohysterectomy.[34][32] Although one study found epidural nalbuphine to provide adequate analgesia there is limited evidence to support epidural administration of nalbuphine.[35][32] Ophthalmic administration is not recommended in any species as multiple studies demonstrated no analgesia following topical ophthalmic administration.[36][37][38][32]
In cats nalbuphine has been shown to provide an equal sedative effect to butorphanol when adminsistered withacepromazine and an equal sedative and analgesic effect when combined withdexmedetomidine andtiltamine-zolazepam respectively.[32][39][40]
In horses evidence is mixed.[32] One study found that nalbuphine combined withxylazine was more effective than xylazine by itself as an analgesic and anaesthetic,[41] but another study found no difference between xylazine itself and xylazine with nalbuphine.[42][32]
Evidence in livestock is limited.[32] One study inHolstein calves following castration found nalbuphine to provide inadequate analgesia and sedation.[43][32] In goats one study found that nalbuphine combined withketamine provided better post-operative analgesia than ketamine by itself at a higher dose.[44][32]
The mean absolute bioavailability was 81% and 83% for the 10 and 20 mg intramuscular doses, respectively, and 79% and 76% following 10 and 20 mg of subcutaneous nalbuphine.
