Nicoboxil

Identification

Summary

Nicoboxil is a medication used to treat acute back pain.

Generic Name

Nicoboxil

DrugBank Accession Number

DB12911

Background

Nicoboxil has been investigated for the treatment of Acute Low Back Pain, where it is typically considered an effective and safe therapeutic option. Nevertheless, it is predominantly found paired with nonivamide as a combination topical analgesic product where its proposed mechanism of action as a rubefacient is complementary and ultimately synergistic with nonivamide's capsaicin activity ⁵. Such combination topical analgesics are only available for purchase and use (for humans) in some parts of Europe and Asia, like Germany and Australia ^5,7.

Despite topical nicoboxil/nonivamide topical analgesic medication being used since the 1950s, recent studies demonstrate continued interest in the medication(s) given its demonstrated efficacy, safety, and capability to be used as an alternative musculoskeletal pain therapy option with less systemic side effects when compared to the oral non-steroidal anti-inflammatory drugs and opioids that may be more typically prescribed ^1,2.

Type

Small Molecule

Groups

Approved, Investigational

Structure

Similar Structures

Weight: Average: 223.272
Monoisotopic: 223.120843411
Chemical Formula: C₁₂H₁₇NO₃

Synonyms

beta-Butoxyethyl nicotinate
Nicoboxil

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Pharmacology

Indication

The primary therapeutic use for which nicoboxil is currently indicated for is as an active ingredient in combination with the capsaicinoid nonivamide compound as a topical analgesic for the temporary relief of the pain of rheumatism, arthritis, lumbago, muscular aches, sprains and strains, sporting injuries, and other conditions where local warmth is beneficial ⁵.

Nevertheless, most of the available studies regarding the use of nicoboxil and nonivamide topical analgesics focus specifically on their efficacy and safety in treating acute non-specific low back pain, typically finding the combination analgesic to be an effective, safe, and well-tolerated medication for such an indication ^1,2.

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Contraindications & Blackbox Warnings

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Pharmacodynamics

Topical applications consisting of the individual active ingredients of nicoboxil and nonivamide at doses considered to be therapeutic are generally not considered readily available commercially ¹. Subsequently, the pharmacodynamics of nicoboxil are considered useful in commercially available combination products largely because they combine with those of nonivamide to offer a synergistic effect from the unique complementary actions of these two agents ⁵.

Subsequently, nonivamide is a synthetic capsaicin analog with analgesic properties which are assumed to result from the depletion of Substance P in the peripheral nociceptive C-fibres and A-delta nerve fibers upon repetitive topical application ⁵. Resultant stimulation of afferent nerve endings in the skin evidently causes a dilatory effect on the surrounding blood vessels accompanied by an intense, long-lasting sensation of warmth associated with the nonivamide use ⁵.

Given the proposed effect of nonivamide, it is believed that nicoboxil is a vitamin of the B complex ⁶ that possesses vasodilating properties facilitated by prostaglandin ⁵. The observed hyperaemic increased blood flow effect of nicoboxil occurs earlier and is described as being more intense than the nonivamide hyperaemic effect ⁵. Nicoboxil and nonivamide are consequently generally indicated as a combination product because the pharmacodynamics of nicoboxil are considered useful as a complement to those of nonivamide, and vice versa ^5,1. In essence, both compounds induce vasodilation by different effects and therefore have complementary abilities inducing increased blood flow, thus hastening the hyperaemic skin reaction ⁷.

Mechanism of action

In particular, nicoboxil is considered a rubefacient ^5,1. However, the specific mechanism of action by which rubefacients like nicoboxil elicit pharmacologic effects has not yet been formally elucidated ^3,4. Nevertheless, it is generally proposed that rubefacients cause irritation of the skin when applied topically, and are believed to alleviate pain in muscles, joints, tendons, and other musculoskeletal pains in the extremities by counter-irritation ³. This specific term, 'counter-irritant', derives from the fact that rubefacients can cause a reddening of the skin by causing the blood vessels of the skin to dilate, which gives a soothing feeling of warmth ³. In essence, the term largely refers to the notion that irritation of the sensory nerve endings alters or offsets pain in the underlying muscle or joints that are innervated by the same nerves ³.

In fact, the vasodilation effect of rubefacients like nicoboxil has been considered the result of nerve conduction mechanisms as early as the late 1950s when certain studies demonstrated that the concomitant application of xylocaine could counteract or prevent the vasolidator response to rubefacients in 50% of such related experiments ⁴.

Absorption

Specific investigations on absorption of dermally applied nicoboxil in laboratory animals or target species were not available ⁶. Published data for nicotinate esters related to nicoboxil indicated however, that members of this class of compounds are in principle able to penetrate skin [12].

Regardless, there is interest in the studies that demonstrate nicoboxil and nonivamide combination topical applications as effective and safe analgesic products precisely because such topical formulations are expected to have much lower systemic absorption - and thus less exposure to systemic side effects (ie. like gastrointestinal upset, drowsiness, etc.) - than the oral non-steroidal anti-inflammatory drugs, opioids, muscle relaxants, and steroids that may be more commonly prescribed over a rubefacient like nicoboxil ^1,2.

Nevertheless, despite the fact that topical nicoboxil and nonivamide products been available to use in some parts of Europe since the 1950s to treat discomfort of the muscuoskeletal system, the effects of nicoboxil and nonivamide have not been investigated in detail and a lack of detailed studies on nicoboxil pharmacodynamics and pharmacokinetics remains ongoing ¹.

Volume of distribution

Despite the fact that topical nicoboxil and nonivamide products been available to use in some parts of Europe since the 1950s to treat discomfort of the muscuoskeletal system, the effects of nicoboxil and nonivamide have not been investigated in detail and a lack of detailed studies on nicoboxil pharmacodynamics and pharmacokinetics remains ongoing ¹. Readily accessible data regarding the volume of distribution of nicoboxil is subsequently not available.

Protein binding

Despite the fact that topical nicoboxil and nonivamide products been available to use in some parts of Europe since the 1950s to treat discomfort of the muscuoskeletal system, the effects of nicoboxil and nonivamide have not been investigated in detail and a lack of detailed studies on nicoboxil pharmacodynamics and pharmacokinetics remains ongoing ¹. Readily accessible data regarding the protein binding of nicoboxil is subsequently not available.

Metabolism

Any systemically absorbed nicoboxil is expected to be hydrolyzed to nicotinic acid and 2-butoxyethanol in blood plasma ⁶. In vitro it is reported that such hydrolysis reactions are catalyzed by esterase-like activity of serum albumin and by plasma esterases ⁶. The nicotinic acid metabolite is also capable of vascular dilatation ⁶. In humans, the urinary elimination of 2-butoxyethanol's metabolite, 2-butoxyacetic acid was also reported ⁶.

The metabolism of nicoboxil is considered to be rapid ⁶.

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Nicoboxil
- 2-butoxyethanol + Niacin

Route of elimination

Following ester cleavage, the nicotinic acid metabolite is expected to enter the endogenous metabolic pool as a part of the vitamin B complex ⁶. The 2-butoxyethanol metabolite is believed to be mainly excreted primarily in the urine and to a certain extent, in exhaled air ⁶. In humans, the urinary elimination of 2-butoxyethanol's metabolite, 2-butoxyacetic acid was also reported ⁶.

Half-life

The half-life of ester hydrolysis was found to be very short in the presence of human serum albumin - less than 15 minutes, 50uM ⁶.

Clearance

The elimination of nicoboxil is considered to be rapid ⁶.

Despite the fact that topical nicoboxil and nonivamide products been available to use in some parts of Europe since the 1950s to treat discomfort of the muscuoskeletal system, the effects of nicoboxil and nonivamide have not been investigated in detail and a lack of detailed studies on nicoboxil pharmacodynamics and pharmacokinetics remains ongoing ¹. Readily accessible data regarding the clearance of nicoboxil is subsequently not available.

Adverse Effects

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Toxicity

Nicoboxil is of low acute toxicity ⁶. No adverse side effects were reported in humans after therapeutic use of the combination of nicoboxil/nonivamide ⁶. In a study using dermal application of nicoboxil/nonivamide in over 1000 patients, no allergic reactions were observed ⁶.

Pathways

Not Available

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Not Available

Interactions

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This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Drug	Interaction
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Tenofovir alafenamide	The serum concentration of Tenofovir alafenamide can be increased when it is combined with Nicoboxil.

Food Interactions

No interactions found.

Products

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Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End
Actinac Pwr	Nicoboxil (24 mg / g) + Allantoin (24 mg / g) + Chloramphenicol (40 mg / g) + Hydrocortisone acetate (40 mg / g) + Octasulfur (320 mg / g)	Powder	Topical	Roussel Canada Inc.	1978-12-31	1996-09-09
Actinac Pws	Nicoboxil (24 mg / g) + Allantoin (24 mg / g) + Chloramphenicol (40 mg / g) + Hydrocortisone acetate (40 mg / g) + Octasulfur (320 mg / g)	Powder, for solution	Topical	Hoechst Roussel Canada Inc.	1994-12-31	2001-07-20
Finalgon - Salbe	Nicoboxil (25 mg) + Nonivamide (4 mg)	Ointment	Topical	Zentiva K.S.	1953-12-07	Not applicable
Nonivamid + Nicoboxil Zentiva 4 mg/g + 25 mg/g Salbe	Nicoboxil (25 mg/g) + Nonivamide (4 mg/g)	Ointment	Cutaneous	Zentiva	2018-04-17	Not applicable

Chemical Identifiers

UNII: GSD5B9US0W
CAS number: 13912-80-6
InChI Key: IZJRISIINLJVBU-UHFFFAOYSA-N
InChI: InChI=1S/C12H17NO3/c1-2-3-7-15-8-9-16-12(14)11-5-4-6-13-10-11/h4-6,10H,2-3,7-9H2,1H3
IUPAC Name: 2-butoxyethyl pyridine-3-carboxylate
SMILES: CCCCOCCOC(=O)C1=CN=CC=C1

References

General References

Gaubitz M, Schiffer T, Holm C, Richter E, Pisternick-Ruf W, Weiser T: Efficacy and safety of nicoboxil/nonivamide ointment for the treatment of acute pain in the low back - A randomized, controlled trial. Eur J Pain. 2016 Feb;20(2):263-73. doi: 10.1002/ejp.719. Epub 2015 Apr 30. [Article]
Blahova Z, Holm JC, Weiser T, Richter E, Trampisch M, Akarachkova E: Nicoboxil/nonivamide cream effectively and safely reduces acute nonspecific low back pain - a randomized, placebo-controlled trial. J Pain Res. 2016 Dec 14;9:1221-1230. doi: 10.2147/JPR.S118329. eCollection 2016. [Article]
Matthews P, Derry S, Moore RA, McQuay HJ: Topical rubefacients for acute and chronic pain in adults. Cochrane Database Syst Rev. 2009 Jul 8;(3):CD007403. doi: 10.1002/14651858.CD007403.pub2. [Article]
FULTON GP, FARBER EM, MORECI AP: The mechanism of action of rubefacients. J Invest Dermatol. 1959 Dec;33:317-25. [Article]
Finalgon Cream (nonivamide and butoxyethyl nicotinate) Label [File]
European Agency for the Evaluation of Medicinal Products Veterinary Medicines Evaluation Unit: Committee for Veterinary Medicinal Products Nicoboxil Summary Report [File]
Bundesinstitut fur Arzneimittel und Medizinprodukte Decentralised Procedure Public Assessment Report: Finalgon 4 mg/g + 25 mg/g Salbe Nonivamide, Nicoboxil [File]

External Links

KEGG Drug: D01677
KEGG Compound: C13138
PubChem Compound: 14866
PubChem Substance: 347829061
ChemSpider: 14176
RxNav: 235788
ChEBI: 32322
ChEMBL: CHEMBL2105161
ZINC: ZINC000002020020

MSDS

Download (34.7 KB)

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
3	Completed	Treatment	Acute Low Back Pain	1
3	Completed	Treatment	Back Pain Lower Back	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Powder	Topical
Powder, for solution	Topical
Ointment	Topical
Ointment	Cutaneous

Prices

Not Available

Patents

Not Available

Properties

State

Not Available

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	6.1 mg/mL	ALOGPS
logP	1.99	ALOGPS
logP	2.04	Chemaxon
logS	-1.6	ALOGPS
pKa (Strongest Basic)	3.24	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	3	Chemaxon
Hydrogen Donor Count	0	Chemaxon
Polar Surface Area	48.42 Å²	Chemaxon
Rotatable Bond Count	8	Chemaxon
Refractivity	60.84 m³·mol^-1	Chemaxon
Polarizability	25.03 Å³	Chemaxon
Number of Rings	1	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0ab9-2940000000-e8dc9406f712d9d0b651
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-00di-9500000000-fc8fde2cf9c584aa74cd
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-004i-9000000000-392105e2e34fe277fb66
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0a4i-2900000000-7b41bb3ec2b37304a8ff
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-004i-9100000000-dfb3e467feceb8f14822
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0a59-9600000000-4b96149bcb89f2a16138
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å²)	Source type	Source
[M-H]-	161.5285532	predicted	DarkChem Lite v0.1.0
[M-H]-	151.92744	predicted	DeepCCS 1.0 (2019)
[M+H]+	162.5378532	predicted	DarkChem Lite v0.1.0
[M+H]+	155.63264	predicted	DeepCCS 1.0 (2019)
[M+Na]+	163.1140532	predicted	DarkChem Lite v0.1.0
[M+Na]+	164.85445	predicted	DeepCCS 1.0 (2019)

Drug created at October 21, 2016 01:12 / Updated at June 12, 2021 10:54

Nicoboxil

Identification

Structure for Nicoboxil (DB12911)

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Collision Cross Sections (CCS)