Nalbuphine

Nalbuphine

Clinical data
AHFS/Drugs.com	Monograph
MedlinePlus	a682668
Pregnancy category	B
Routes of administration	intravenous, intramuscular, subcutaneous
ATC code	N02AF02 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) CA: Schedule IV US: ℞-only
Pharmacokinetic data
Bioavailability	81% (10mg), 83% (20 mg), intramuscular; 79% (10mg), 76% (20 mg)
Metabolism	hepatic
Biological half-life	≈5 hours (3-6)
Excretion	93% in 6 hours
Identifiers
IUPAC name (–)-17-(cyclobutylmethyl)- 4,5α-epoxymorphinan- 3,6α,14-triol
CAS Number	20594-83-6 Y
PubChem (CID)	5311304
IUPHAR/BPS	1663
DrugBank	DB00844 Y
ChemSpider	4470813 Y
UNII	L2T84IQI2K Y
ChEBI	CHEBI:7454 Y
ChEMBL	CHEMBL895 Y
ECHA InfoCard	100.039.895
Chemical and physical data
Formula	C21H27NO4
Molar mass	357.443 g/mol
3D model (Jmol)	Interactive image
SMILES O[C@@H]4[C@@H]5Oc1c2c(ccc1O)C[C@H]3N(CC[C@]25[C@@]3(O)CC4)CC6CCC6
InChI InChI=1S/C21H27NO4/c23-14-5-4-13-10-16-21(25)7-6-15(24)19-20(21,17(13)18(14)26-19)8-9-22(16)11-12-2-1-3-12/h4-5,12,15-16,19,23-25H,1-3,6-11H2/t15-,16+,19-,20-,21+/m0/s1 Y Key:NETZHAKZCGBWSS-CEDHKZHLSA-N Y
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Nalbuphine is a semi-synthetic opioid used commercially as an analgesic under a variety of trade names, including Nubain and Manfine.

Medical uses

Nalbuphine is indicated for the relief of moderate to severe pain. It can also be used as a supplement to balanced anesthesia, for preoperative and postoperative analgesia, and for obstetrical analgesia during labor and delivery.

Although 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. Therefore, patients receiving an opioid analgesic, general anesthetics, phenothiazines, or other tranquilizers, sedatives, hypnotics, or other CNS depressants (including alcohol) concomitantly with Nalbuphine may exhibit an additive effect. When such combined therapy is contemplated, the dose of one or both agents should be reduced.

In addition to the relief of pain, the drug has been studied as a treatment for morphine induced pruritus (itching). Pruritus is a common side effect of morphine or other pure mu agonist opioid administration. Kjellberg et al. (2001) published a review of clinical trials relating to the prevalence of morphine induced pruritus and its pharmacologic control. The authors state that nalbuphine is an effective anti-pruritic agent against morphine induced pruritus. The effect may be mediated via central nervous system mechanisms.

Pan (1998) summarizes the evidence that activation at the pharmacological level of the opioid κ-receptor antagonizes various opioid μ-receptor mediated actions in the brain. The authors states that the neural mechanism for this potentially very general opioid μ-receptor antagonizing function by the opioid κ-receptor may have broad applications in the treatment of central nervous system mediated diseases. He does not state, however, that nalbuphine's pharmacological mechanism of action for pruritus is the result of this interaction between the two opioid receptors.

Morphine induced pruritus syndrome may also be caused by release of histamine from mast cells in the skin (Gunion et al. (2004). Paus et al. (2006) report that opioid μ-receptors and opioid κ-receptors 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 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.

Overdose

In case of overdose or adverse reaction, the immediate intravenous administration of naloxone (Narcan) is a specific antidote. Oxygen, intravenous fluids, vasopressors and other supportive measures should be used as indicated.

Side effects

Like pure µ-opioids, the mixed agonists-antagonist opioid class of drugs can cause side effects with initial administration of the drug but which lessen over time (“tolerance”). This is particularly true for the side effects of nausea, sedation and cognitive symptoms (Jovey et al. 2003). These 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. An important difference between nalbuphine and the pure mu opioid analgesic drugs is the “ceiling effect” on respiration. Respiratory depression is a potentially fatal side effect from the use of pure mu opioids. Nalbuphine has limited ability to depress respiratory function (Gal et al. 1982).

As reported in the current Nubain Package Insert (2005), the most frequent side effect in 1066 patients treated with nalbuphine was sedation in 381 (36%).

Other, 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%). Other adverse reactions which may occur (reported incidence of 1% or less) are:

• CNS effects: Nervousness, depression, restlessness, crying, euphoria, floating, hostility, unusual dreams, confusion, faintness, hallucinations, dysphoria, feeling of heaviness, numbness, tingling, unreality. The incidence of psychotomimetic effects, such as unreality, depersonalization, delusions, dysphoria and hallucinations has been shown to be less than that which occurs with pentazocine.
• Cardiovascular: Hypertension, hypotension, bradycardia, tachycardia, pulmonary edema.
• Gastrointestinal: Cramps, dyspepsia, bitter taste.
• Respiration: Depression, dyspnea, asthma.
• Dermatological: Itching, burning, urticaria.
• Obstetric: Pseudo-sinusoidal fetal heart rhythm.

Other possible, but rare side effects include speech difficulty, urinary urgency, blurred vision, flushing and warmth.

History and control status

In the search for opioid analgesics with less abuse potential than pure mu agonist opioids, a number of semi-synthetic opiates were developed. These substances are referred to as mixed agonist–antagonists analgesics. Nalbuphine (brand name Nubain, Raltrox) belongs to this group of substances. The mixed agonists-antagonists drug class exerts their analgesic actions by agonistic activity at opioid kappa (“κ”) receptors. While all drugs in this class possess opioid mu (“μ”) receptor 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 opiate receptors as a full mu antagonist as well as a full kappa agonist. (Gustein et al. 2001).

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 the Controlled Substances Act (CSA). When the Controlled Substances Act (CSA) was enacted in 1971, nalbuphine was placed in schedule 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 the Department 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.

Nalbuphine HCL is currently only available as an injectable in the US and the European Union. Nubain, the 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.

Clinical pharmacology

Nalbuphine is a semi-synthetic opioid agonist-antagonist analgesic of the phenanthrene series. It is chemically related to the widely used opioid antagonists, naloxone and naltrexone, and the potent opioid analgesic, oxymorphone. It 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. The 10 mg/mL strength contains 0.1% sodium chloride.

Nalbuphine is also available in a 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. The 10 mg/mL strength contains 0.2% sodium chloride. Nalbuphine is a potent analgesic. Its analgesic potency is essentially equivalent to that of morphine on a milligram basis 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 15–60 mg range had similar analgesic effects to immediate release codeine 30–60 mg range (Kantor et al. 1984), (Sunshine et al. 1983). Its onset of action occurs within 2 to 3 minutes after intravenous administration, and in less than 15 minutes following subcutaneous or intramuscular injection. The plasma half-life of nalbuphine is 5 hours and in clinical studies the duration of analgesic activity has been reported to range from 3 to 6 hours.

Schmidt et al. (1985) reviews nalbuphine’s pre-clinical pharmacology and report comparative data relative to other types of opioid compounds. The authors point out that the nalbuphine moiety is approximately ten times more pharmacologically potent than the mixed opioid agonist-antagonist butorphanol on an “antagonist index” scale which quantitates the drug’s ability to act both as an analgesic (via opioid κ-receptor agonism) as well as an μ-receptor antagonist. The opioid antagonist activity of Nalbuphine is one-fourth as potent as nalorphine and 10 times that of pentazocine.

Activity profile

Nalbuphine binds with high affinity to the μ-opioid receptor (K_i = 0.89 nM) and κ-opioid receptor (K_i = 2.2 nM), and has relatively low affinity for the δ-opioid receptor (K_i = 240 nM). It behaves as a moderate-efficacy partial agonist (or mixed agonist-antagonist) of the μ-opioid receptor (IA = 47%; EC₅₀ = 14 nM) and as a high-efficacy partial agonist of the κ-opioid receptor (IA = 81%; EC₅₀ = 27 nM).

Marketing

This drug is marketed under the brand name Raltrox in Bangladesh by Opsonin Pharma Limited.

It is also marketed under the brand name Rubuphine in India by Rusan Healthcare Pvt Ltd.

It is also marketed under the brand name Kinz and Nalbin in Pakistan by Sami and Global Pharmaceuticals. Medicaids Pakistan also markets the product under the brand name of ANALIN, while Another local pharmaceutical company Indus Pharma, has recently launched Nalbuphine with brand name of EXNAL .

See also

• Butorphanol
• Levallorphan
• Nalmefene
• Nalodeine
• Nalorphine
• Xorphanol

References

• Beaver WT, Feise GA. A comparison of the analgesic effect of intramuscular nalbuphine and morphine in patients with postoperative pain. The Journal of Pharmacology and Experimental Therapeutics. 1978;204(2):487-496.
• Kantor TG, Hopper M. Oral nalbuphine and codeine in patients with postoperative pain. Clin Pharmacol Ther 1984;35:46-49.
• Federal Register. November 2008. Nubain Withdrawal.
• Gal TJ, DiFazio CA, et al. Analgesic and respiratory depressant activity of nalbuphine: a comparison with morphine. Anesthesiology. 1982;57:367-374.
• Gunion MW, Marchionne A, Anderson CTM. Use of the mixed agonist-antagonist nalbuphine in opioid based analgesia. Acute Pain (2004) 6, 29-39
• Gutstein H, Akil H. Chapter 23: Opioid Analgesics. In: Goodman & Gilman’s The Pharmacologic Basis of Therapeutics. 10th Edition. Edited by Hardman J and Limbird L. McGraw Hill. 2001.
• Jovey RD et al. Use of opioid analgesics for the treatment of chronic non-cancer pain. Pain Res Manage. 2003; 8 (Suppl A):3A-14A.
• Kjellberg F, Tramèr MR. Pharmacological control of opioid-induced pruritus: a quantitative systematic review of randomized trials. Eur J Anaesthesiol. 2001 Jun;18(6):346-57
• Levy JH, Brister NW, Shearin A, Ziegler J, Hug CC Jr, Adelson DM, Walker BF. Wheal and flare responses to opioids in humans. Anesthesiology. 1989 May;70(5):756-60.
• Nubain Package Insert. Endo Pharmaceuticals. 51-022542-01. January 2005
• Okun R. Analgesic effects of oral nalbuphine and codeine in patients with postoperative pain. Clin Pharmacol Ther. 1982;32(4):517-524.
• Pan ZZ. μ- Opposing actions of the κ- opioid receptor. TiPS. 1998;19:94-98.
• Paus et al., Frontiers in Pruritus Research. Journal of Clinical Investigation. 2006; 116:1174-1185
• Schmidt et al., Nalbuphine. Drugs and Alcohol Dependence. 1985;14:339-362.
• Sunshine A, Zighelboim I, et al. A study of the analgesic efficacy of nalbuphine hydrochloride in patients with post-partum pain. Curr Ther Res 1983;33:108-114.
• Voronkov M, Ocherer D, Bondarenko S, Yu Y, Koren S. Administration of Nalbuphine to Heroin Addicts. Feasibility and Short Term Effects. Heroin Addict Relat Clin Probl 2008; 10(1): 19-24

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