Nefopam

Last updated
Nefopam
Nefopam2DACS.svg
Nefopam ball-and-stick model.png
Clinical data
Trade names nefopam medisol
AHFS/Drugs.com International Drug Names
Routes of
administration 		intramuscular, intravenous
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
Pharmacokinetic data
Bioavailability Low [1]
Protein binding 70–75% (mean 73%) [1] [2]
Metabolism Liver (N-demethylation, others) [1]
Metabolites Desmethylnefopam, others [1]
Elimination half-life Nefopam: 3–8 hours [1]
Desmethylnefopam: 10–15 hours [1]
Excretion Urine: 79.3% [1]
Feces: 13.4% [1]
Identifiers
  • (RS)-5-methyl-1-phenyl-1,3,4,6-tetrahydro-2,5-benzoxazocine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
CompTox Dashboard (EPA)
ECHA InfoCard 100.033.757 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C17H19NO
Molar mass 253.345 g·mol−1
3D model (JSmol)
  • CN1CCOC(C2=CC=CC=C2C1)C3=CC=CC=C3
  • InChI=1S/C17H19NO/c1-18-11-12-19-17(14-7-3-2-4-8-14)16-10-6-5-9-15(16)13-18/h2-10,17H,11-13H2,1H3 X mark.svgN
  • Key:RGPDEAGGEXEMMM-UHFFFAOYSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Nefopam, sold under the brand name Acupan among others, is a centrally acting, non-opioid painkilling medication, with central stimulant and sympathomimetic properties that is primarily used to treat moderate to severe pain. [3]

Contents

Nefopam acts in the brain and spinal cord to relieve pain via novel mechanisms: antinociceptive effects from triple monoamine reuptake inhibition, and antihyperalgesic activity through modulation of glutamatergic transmission. [4]

Medical uses

Nefopam is effective for prevention of shivering during surgery or recovery from surgery. [5] [6] Nefopam was significantly more effective than aspirin as an analgesic in one clinical trial, [7] although with a greater incidence of side effects such as sweating, dizziness and nausea, especially at higher doses. [8] [9] The estimated relative potency of nefopam to morphine indicates that 20 mg of nefopam HCl is the approximate analgesic equal of 12 mg of morphine with comparable analgesic efficacy to morphine, [10] [11] [12] or oxycodone, [13] while nefopam tends to produce fewer side effects, does not produce respiratory depression, [14] and has much less abuse potential, and so is useful either as an alternative to opioid analgesics, or as an adjunctive treatment for use alongside opioids or other types of analgesics. [12] [15] Nefopam is also used to treat severe hiccups. [16] Nefopam is also used for the manufacture of a medicament for the treatment of an affective disorder and attention-deficit disorder. [17] Nefopam can also be used as a contradiction for the treatment of Parkinson’s disease. [18]

Contraindications

Nefopam is contraindicated in people with convulsive disorders, those that have received treatment with irreversible monoamine oxidase inhibitors such as phenelzine, tranylcypromine or isocarboxazid within the past 30 days and those with myocardial infarction pain, mostly due to a lack of safety data in these conditions. [19]

Side effects

Common side effects include nausea, nervousness, dry mouth, light-headedness and urinary retention. [19] Less common side effects include vomiting, blurred vision, drowsiness, sweating, insomnia, headache, confusion, hallucinations, tachycardia, aggravation of angina and rarely a temporary and benign pink discolouration of the skin or erythema multiforme. [19]

Overdose

Overdose and death have been reported with nefopam. [20] Overdose usually manifests with convulsions, hallucinations, tachycardia, and hyperdynamic circulation. [19] Treatment is usually supportive, managing cardiovascular complications with beta blockers and limiting absorption with activated charcoal. [19]

Interactions

It has additive anticholinergic and sympathomimetic effects with other agents with these properties. [19] Its use should be avoided in people receiving some types of antidepressants (tricyclic antidepressants or monoamine oxidase inhibitors) as there is the potential for serotonin syndrome or hypertensive crises to result. [19]

Pharmacology

Nefopam [21] [22]
SiteKi (nM)
SERT Tooltip Serotonin transporter29
NET Tooltip Norepinephrine transporter33
DAT Tooltip Dopamine transporter531
5-HT2A 1,685
5-HT2B 330
5-HT2C 56

Pharmacodynamics

The mechanism of action of nefopam and its analgesic effects are not well understood, although inhibition of the reuptake of serotonin, norepinephrine, and dopamine (that is, acting as an SNDRI Tooltip serotonin–norepinephrine–dopamine reuptake inhibitor) is thought to be involved. [23] [4] It also reduces glutamate signaling via modulating sodium and calcium channels. [24] [4]

Pharmacokinetics

The absolute bioavailability of nefopam is low. [1] It is reported to achieve therapeutic plasma concentrations between 49 and 183 nM. [22] The drug is approximately 73% protein-bound across a plasma range of 7 to 226 ng/mL (28–892 nM). [1] The metabolism of nefopam is hepatic, by N-demethylation and via other routes. [1] Its terminal half-life is 3 to 8 hours, while that of its active metabolite, desmethylnefopam, is 10 to 15 hours. [1] It is eliminated mostly in urine, and to a lesser extent in feces. [1]

Chemistry

Nefopam is a cyclized analogue of orphenadrine, diphenhydramine, and tofenacin, with each of these compounds different from one another only by the presence of one or two carbons. [25] [26] [27] The ring system of nefopam is a benzoxazocine system. [25] [28]

Society and culture

Recreational use

Recreational use of nefopam has rarely been reported, [20] and is far less common than with opioid analgesics. [29]

Names

In the 1960s, when it was first developed, it had the generic name fenazoxine. [24]

See also

Related Research Articles

<span class="mw-page-title-main">Analgesic</span> Drugs used to achieve relief from pain

An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in some instances eliminate, sensation, although analgesia and anesthesia are neurophysiologically overlapping and thus various drugs have both analgesic and anesthetic effects.

<span class="mw-page-title-main">Hydrocodone</span> Opioid drug used in pain relief

Hydrocodone, also known as dihydrocodeinone, is a semi-synthetic opioid used to treat pain and as a cough suppressant. It is taken by mouth. Typically, it is dispensed as the combination acetaminophen/hydrocodone or ibuprofen/hydrocodone for pain severe enough to require an opioid and in combination with homatropine methylbromide to relieve cough. It is also available by itself in a long-acting form sold under the brand name Zohydro ER, among others, to treat severe pain of a prolonged duration. Hydrocodone is a controlled drug: in the United States, it is classified as a Schedule II Controlled Substance.

<span class="mw-page-title-main">Tricyclic antidepressant</span> Class of medications

Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants. TCAs were discovered in the early 1950s and were marketed later in the decade. They are named after their chemical structure, which contains three rings of atoms. Tetracyclic antidepressants (TeCAs), which contain four rings of atoms, are a closely related group of antidepressant compounds.

<span class="mw-page-title-main">Tramadol</span> Opioid pain medication

Tramadol, sold under the brand name Ultram among others, is an opioid pain medication and a serotonin–norepinephrine reuptake inhibitor (SNRI) used to treat moderately severe pain. When taken by mouth in an immediate-release formulation, the onset of pain relief usually begins within an hour. It is also available by injection. It is available in combination with paracetamol (acetaminophen).

<span class="mw-page-title-main">Hydromorphone</span> Opioid medication used for pain relief

Hydromorphone, also known as dihydromorphinone, and sold under the brand name Dilaudid among others, is a morphinan opioid used to treat moderate to severe pain. Typically, long-term use is only recommended for pain due to cancer. It may be used by mouth or by injection into a vein, muscle, or under the skin. Effects generally begin within half an hour and last for up to five hours. A 2016 Cochrane review found little difference in benefit between hydromorphone and other opioids for cancer pain.

<span class="mw-page-title-main">Duloxetine</span> Antidepressant medication used also for the treatment of anxiety and chronic pain


Duloxetine, sold under the brand name Cymbalta among others, is a medication used to treat major depressive disorder, generalized anxiety disorder, obsessive-compulsive disorder, fibromyalgia, neuropathic pain and central sensitization. It is taken by mouth.

<span class="mw-page-title-main">Pethidine</span> Opioid analgesic

Pethidine, also known as meperidine and sold under the brand name Demerol among others, is a fully synthetic opioid pain medication of the phenylpiperidine class. Synthesized in 1938 as a potential anticholinergic agent by the German chemist Otto Eisleb, its analgesic properties were first recognized by Otto Schaumann while working for IG Farben, in Germany. Pethidine is the prototype of a large family of analgesics including the pethidine 4-phenylpiperidines, the prodines, bemidones, and others more distant, including diphenoxylate and analogues.

<span class="mw-page-title-main">Serotonin–norepinephrine reuptake inhibitor</span> Class of antidepressant medication

Serotonin–norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant medications used to treat major depressive disorder (MDD), anxiety disorders, social phobia, chronic neuropathic pain, fibromyalgia syndrome (FMS), and menopausal symptoms. Off-label uses include treatments for attention-deficit hyperactivity disorder (ADHD), and obsessive–compulsive disorder (OCD). SNRIs are monoamine reuptake inhibitors; specifically, they inhibit the reuptake of serotonin and norepinephrine. These neurotransmitters are thought to play an important role in mood regulation. SNRIs can be contrasted with the selective serotonin reuptake inhibitors (SSRIs) and norepinephrine reuptake inhibitors (NRIs), which act upon single neurotransmitters.

<span class="mw-page-title-main">Buprenorphine</span> Opioid used to treat pain & opioid use disorder

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Functional selectivity is the ligand-dependent selectivity for certain signal transduction pathways relative to a reference ligand at the same receptor. Functional selectivity can be present when a receptor has several possible signal transduction pathways. To which degree each pathway is activated thus depends on which ligand binds to the receptor. Functional selectivity, or biased signaling, is most extensively characterized at G protein coupled receptors (GPCRs). A number of biased agonists, such as those at muscarinic M2 receptors tested as analgesics or antiproliferative drugs, or those at opioid receptors that mediate pain, show potential at various receptor families to increase beneficial properties while reducing side effects. For example, pre-clinical studies with G protein biased agonists at the μ-opioid receptor show equivalent efficacy for treating pain with reduced risk for addictive potential and respiratory depression. Studies within the chemokine receptor system also suggest that GPCR biased agonism is physiologically relevant. For example, a beta-arrestin biased agonist of the chemokine receptor CXCR3 induced greater chemotaxis of T cells relative to a G protein biased agonist.

<span class="mw-page-title-main">Zomepirac</span> Withdrawn non-steroidal anti-inflammatory drug

Zomepirac is an orally effective nonsteroidal anti-inflammatory drug (NSAID) that has antipyretic actions. It was developed by McNeil Pharmaceutical, approved by the FDA in 1980, and sold as the sodium salt zomepirac sodium, under the brand name Zomax. Due to its clinical effectiveness, it was preferred by doctors in many situations and obtained a large share of the analgesics market; however, it was subsequently withdrawn in March 1983 due to its tendency to cause serious anaphylaxis in a small, but unpredictable, subset of the patient population.

<span class="mw-page-title-main">Desmetramadol</span> Opioid painkiller medication

Desmetramadol, also known as O-desmethyltramadol (O-DSMT), is an opioid analgesic and the main active metabolite of tramadol. Tramadol is demethylated by the liver enzyme CYP2D6 to desmetramadol in the same way as codeine, and so similarly to the variation in effects seen with codeine, individuals who have a less active form of CYP2D6 will tend to have reduced analgesic effects from tramadol. Because desmetramadol itself does not need to be metabolized to induce an analgesic effect, it can be used in individuals with low CYP2D6 activity unlike tramadol.

<span class="mw-page-title-main">Serotonin reuptake inhibitor</span> Class of drug

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<span class="mw-page-title-main">Tapentadol</span> Opioid analgesic of benzenoid class

Tapentadol, sold under the brand names Nucynta and Palexia among others, is a synthetic opioid analgesic of the benzenoid class with a dual mode of action as a highly selective full agonist of the μ-opioid receptor and as a norepinephrine reuptake inhibitor (NRI). Tapentadol is used medically for the treatment of moderate to severe pain. It is addictive, a commonly abused drug, and poses a high risk of physical and/or mental dependence.

<span class="mw-page-title-main">Dezocine</span> Opioid analgesic

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References

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  5. ↑ Kang P, Park SK, Yoo S, Hur M, Kim WH, Kim JT, Bahk JH (January 2019). "Comparative effectiveness of pharmacologic interventions to prevent shivering after surgery: a network meta-analysis". Minerva Anestesiologica. 85 (1): 60–70. doi:10.23736/S0375-9393.18.12813-6. PMID   30226340. S2CID   52288008.
  6. ↑ Alfonsi P, Adam F, Passard A, Guignard B, Sessler DI, Chauvin M (January 2004). "Nefopam, a nonsedative benzoxazocine analgesic, selectively reduces the shivering threshold in unanesthetized subjects". Anesthesiology. 100 (1): 37–43. doi:10.1097/00000542-200401000-00010. PMC   1283107 . PMID   14695722.
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  11. ↑ Phillips G, Vickers MD (October 1979). "Nefopam in postoperative pain". British Journal of Anaesthesia. 51 (10): 961–5. doi: 10.1093/bja/51.10.961 . PMID   391253.
  12. 1 2 Heel RC, Brogden RN, Pakes GE, Speight TM, Avery GS (April 1980). "Nefopam: a review of its pharmacological properties and therapeutic efficacy". Drugs. 19 (4): 249–67. doi:10.2165/00003495-198019040-00001. PMID   6991238. S2CID   24713213.
  13. ↑ Tigerstedt I, Tammisto T, Leander P (December 1979). "Comparison of the analgesic dose-effect relationships of nefopam and oxycodone in postoperative pain". Acta Anaesthesiologica Scandinavica. 23 (6): 555–60. doi:10.1111/j.1399-6576.1979.tb01486.x. PMID   397711. S2CID   40976610.
  14. ↑ Gasser JC, Bellville JW (August 1975). "Respiratory effects of nefopam". Clinical Pharmacology and Therapeutics. 18 (2): 175–9. doi:10.1002/cpt1975182175. PMID   1097153. S2CID   22220503.
  15. ↑ Kapfer B, Alfonsi P, Guignard B, Sessler DI, Chauvin M (January 2005). "Nefopam and ketamine comparably enhance postoperative analgesia". Anesthesia and Analgesia. 100 (1): 169–74. doi:10.1213/01.ANE.0000138037.19757.ED. PMC   1283103 . PMID   15616073.
  16. ↑ Bilotta F, Rosa G (December 2000). "Nefopam for severe hiccups". The New England Journal of Medicine. 343 (26): 1973–4. doi: 10.1056/nejm200012283432619 . PMID   11186682.
  17. ↑ WO2007012870A2,Lyne, Michael Harvey&Bannister, Robin Mark,"Use of nefopam for the treatment of affective disorders",issued 2007-02-01
  18. ↑ Beśka, Magdalena; Walawender, Izabela; Kasperski, Jacek; Skaba, Dariusz; Nowak, Przemysław; Reichman-Warmusz, Edyta; Szkilnik, Ryszard; Właściwości, Biologiczne; Przeciwbólowego, Leku; Szczurów, U (January 2010). "Biological Peculiarities of the Analgesic Drug Nefopam in Rats". Advances in Clinical and Experimental Medicine . 1 (19). Retrieved 18 December 2024– via ResearchGate.
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  21. ↑ Roth BL, Driscol J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
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  23. ↑ "New Zealand Data Sheet Acupan(TM)" (PDF). Medsafe. New Zealand The Ministry of Health. 17 May 2017. Retrieved 4 September 2017.
  24. 1 2 Kim KH, Abdi S (April 2014). "Rediscovery of nefopam for the treatment of neuropathic pain". The Korean Journal of Pain. 27 (2): 103–11. doi:10.3344/kjp.2014.27.2.103. PMC   3990817 . PMID   24748937.
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  26. ↑ Sneader W (23 June 2005). Drug Discovery: A History. John Wiley & Sons. pp. 405–. ISBN   978-0-471-89979-2.
  27. ↑ Kubinyi H, Müller G (6 March 2006). Chemogenomics in Drug Discovery: A Medicinal Chemistry Perspective. John Wiley & Sons. pp. 54–. ISBN   978-3-527-60402-9.
  28. ↑ Cruz A (2014). Therapeutic Hypothermia. CRC Press. pp. 176–.
  29. ↑ Tracqui A, Berthelon L, Ludes B (May 2002). "Fatal overdosage with nefopam (Acupan)". Journal of Analytical Toxicology. 26 (4): 239–43. doi: 10.1093/jat/26.4.239 . PMID   12054367.
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