Hydrocodone

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Hydrocodone, also known as dihydrocodeinone, is a semi-synthetic opioid used to treat pain and as a cough suppressant.<ref name="AHFS2019">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It is taken by mouth.<ref name="AHFS2019" /> Typically, it is dispensed as the combination acetaminophen/hydrocodone or ibuprofen/hydrocodone for pain severe enough to require an opioid<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Bri2011">Template:Cite book</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and in combination with homatropine methylbromide to relieve cough.<ref name="AHFS2019" /> 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.<ref name="AHFS2019" /><ref name="Med2019">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Hydrocodone is a controlled drug: in the United States, it is classified as a Schedule II Controlled Substance.

Common side effects include dizziness, sleepiness, nausea, and constipation.<ref name="AHFS2019" /> Serious side effects may include low blood pressure, seizures, QT prolongation, respiratory depression, and serotonin syndrome.<ref name=AHFS2019/> Rapidly decreasing the dose may result in opioid withdrawal.<ref name=AHFS2019/> Use during pregnancy or breastfeeding is generally not recommended.<ref name=Preg2019>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Hydrocodone is believed to work by activating opioid receptors, mainly in the brain and spinal cord.<ref name=AHFS2019/> Hydrocodone 10 mg is equivalent to about 10 mg of morphine by mouth.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Hydrocodone was patented in 1923, while the long-acting formulation was approved for medical use in the United States in 2013.<ref name=AHFS2019/><ref name=Fis2006 /> It is most commonly prescribed in the United States, which consumed 99% of the worldwide supply as of 2010.<ref>Template:Cite newsTemplate:Cbignore</ref> In 2018, it was the 402nd most commonly prescribed medication in the United States, with more than 400,000 prescriptions.<ref name="Hydrocodone - Drug Usage Statistics">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Hydrocodone is a semisynthetic opioid, converted from codeine<ref>Template:Cite book</ref><ref>Template:Cite book</ref> or less often from thebaine.<ref>Template:Cite book</ref> Production using genetically engineered yeasts has been developed but is not used commercially.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Medical uses

Hydrocodone is used to treat moderate to severe pain. In liquid formulations, it is used to treat cough.<ref name=AHFS2019/> In one study comparing the potency of hydrocodone to that of oxycodone, it was found that it took 50% more hydrocodone to achieve the same degree of miosis (pupillary contraction).<ref name="pmid19118954">Template:Cite journal</ref> The investigators interpreted this to mean that oxycodone is about 50% more potent than hydrocodone.

However, in a study of emergency department patients with fractures, it was found that an equal amount of either drug provided about the same degree of pain relief, indicating that there is little practical difference between them when used for that purpose.<ref name="pmid15805317">Template:Cite journal</ref> Some references state that the analgesic action of hydrocodone begins in 20–30 minutes and lasts about 4–8 hours.<ref name="pmid21785485">Template:Cite journal</ref> The manufacturer's information says onset of action is about 10–30 minutes and duration is about 4–6 hours.<ref name="Drugs.com-MMX-Vicodin">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Recommended dosing interval is 4–6 hours. Hydrocodone reaches peak serum levels after 1.3 hours.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Available forms

Hydrocodone is available in a variety of formulations for oral administration:<ref name="McPherson2009">Template:Cite book</ref><ref name="Odom-ForrenDrain2008">Template:Cite book</ref><ref name="Skidmore-Roth2013">Template:Cite book</ref>

• The original oral form of hydrocodone alone, Dicodid, as immediate-release 5- and 10-mg tablets is available for prescription in Continental Europe per national drug control and prescription laws and Title 76 of the Schengen Treaty, but dihydrocodeine has been more widely used for the same indications since the beginning in the early 1920s, with hydrocodone being regulated the same way as morphine in the German Betäubungsmittelgesetz, the similarly named law in Switzerland and the Austrian Suchtmittelgesetz, whereas dihydrocodeine is regulated like codeine. For a number of decades, the liquid hydrocodone products available have been cough medicines.
• Hydrocodone plus homatropine (Hycodan) in the form of small tablets for coughing and especially neuropathic moderate pain (the homatropine, an anticholinergic, is useful in both of those cases and is a deterrent to intentional overdose) was more widely used than Dicodid and was labelled as a cough medicine in the United States whilst Vicodin and similar drugs were the choices for analgesia.
• Extended-release hydrocodone in a time-release syrup also containing chlorphenamine/chlorpheniramine is a cough medicine called Tussionex in North America. In Europe, similar time-release syrups containing codeine (numerous), dihydrocodeine (Paracodin Retard Hustensaft), nicocodeine (Tusscodin), thebacon, acetyldihydrocodeine, dionine, and nicodicodeine are used instead.
• Immediate-release hydrocodone with paracetamol (acetaminophen) (Vicodin, Lortab, Lorcet, Maxidone, Norco, Zydone)
• Immediate-release hydrocodone with ibuprofen (Vicoprofen, Ibudone, Reprexain)
• Immediate-release hydrocodone with aspirin (Alor 5/500, Azdone, Damason-P, Lortab ASA, Panasal 5/500)
• Controlled-release hydrocodone (Hysingla ER by Purdue Pharma, Zohydro ER)<ref name="VadiveluSchermer2016">Template:Cite journal</ref>

Hydrocodone is not available in parenteral or any other non-oral forms.<ref name="ChabnerLongo2010" /><ref name="ElliottSmith2016" />

Side effects

File:Main symptoms of Hydrocodone overdose.svg

Main symptoms of Hydrocodone overdose

Common side effects of hydrocodone are nausea, vomiting, constipation, drowsiness, dizziness, lightheadedness, anxiety, abnormally happy or sad mood, dry throat, difficulty urinating, rash, itching, and contraction of the pupils. Serious side effects include slowed or irregular breathing and chest tightness.<ref name="MedlinePlus">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Several cases of progressive bilateral hearing loss unresponsive to steroid therapy have been described as an infrequent adverse reaction to hydrocodone/paracetamol misuse. This adverse effect has been considered by some to be due to the ototoxicity of hydrocodone.<ref name="pmid10733182">Template:Cite journal</ref><ref name="pmid17525781">Template:Cite journal</ref> Other researchers have suggested that paracetamol is the primary agent responsible for the ototoxicity.<ref name="pmid20493351">Template:Cite journal</ref><ref name="pmid20193831">Template:Cite journal</ref>

The U.S. Food and Drug Administration (FDA) assigns the drug to pregnancy category C, meaning that no adequate and well-controlled studies in humans have been conducted. A newborn of a mother taking opioid medications regularly prior to the birth will be physically dependent.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The baby may also exhibit respiratory depression if the opioid dose was high.<ref name="DailyMed-Reprexain" /> An epidemiological study indicated that opioid treatment during early pregnancy results in increased risk of various birth defects.<ref name="pmid21345403">Template:Cite journal</ref>

Symptoms of hydrocodone overdose include narrowed or widened pupils; slow, shallow, or stopped breathing; slowed or stopped heartbeat; cold, clammy, or blue skin; excessive sleepiness; loss of consciousness; seizures; or death.<ref name="MedlinePlus" />

Hydrocodone can be habit forming, causing physical and psychological dependence. Its abuse liability is similar to morphine and less than oxycodone.<ref name="pmid22992943">Template:Cite journal</ref>

Interactions

Hydrocodone is metabolized by the cytochrome P450 enzymes CYP2D6 and CYP3A4, and inhibitors and inducers of these enzymes can modify hydrocodone exposure.<ref name="pmid28579821">Template:Cite journal</ref> One study found that combination of paroxetine, a selective serotonin reuptake inhibitor (SSRI) and strong CYP2D6 inhibitor, with once-daily extended-release hydrocodone, did not modify exposure to hydrocodone or the incidence of adverse effects.<ref name="pmid28579821" /><ref name="pmid26350273">Template:Cite journal</ref> These findings suggest that hydrocodone can be coadministered with CYP2D6 inhibitors without dosage modification.<ref name="pmid28579821" /><ref name="pmid26350273" /> Conversely, combination of hydrocodone/acetaminophen with the antiviral regimen of ombitasvir, paritaprevir, ritonavir, and dasabuvir for treatment of hepatitis C increased peak concentrations of hydrocodone by 27%, total exposure by 90%, and elimination half-life from 5.1Template:Nbsphours to 8.0Template:Nbsphours.<ref name="pmid26895022">Template:Cite journal</ref> Ritonavir is a strong CYP3A4 inhibitor as well as inducer of CYP3A and other enzymes, and the other antivirals are known to inhibit drug transporters like organic anion transporting polypeptide (OATP) 1B1 and 1B3, P-glycoprotein, and breast cancer resistance protein (BCRP).<ref name="pmid26895022" /> The changes in hydrocodone levels are consistent with CYP3A4 inhibition by ritonavir.<ref name="pmid26895022" /> Based on these findings, a 50% lower dose of hydrocodone and closer clinical monitoring was recommended when hydrocodone is used in combination with this antiviral regimen.<ref name="pmid26895022" />

People consuming alcohol, other opioids, anticholinergic antihistamines, antipsychotics, anxiolytics, or other central nervous system (CNS) depressants together with hydrocodone may exhibit an additive CNS depression.<ref name="DailyMed-Reprexain">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Hydrocodone taken concomitantly with serotonergic medications like SSRI antidepressants may increase the risk of serotonin syndrome.<ref name="pmid15948273">Template:Cite journal</ref>

Pharmacology

Pharmacodynamics

Hydrocodone (and metabolite) at opioid receptors

Compound	Affinities (Template:Abbrlink)			Ratio	Ref
	Template:Abbrlink	Template:Abbrlink	Template:Abbrlink	MOR:DOR:KOR
Hydrocodone	11.1 nM	962 nM	501 nM	1:87:45	<ref name="pmid7562497">Template:Cite journal</ref>
Hydromorphone	0.47 nM	18.5 nM	24.9 nM	1:39:53	<ref name="pmid11197347">Template:Cite journal</ref>

Equivalent analgesia doses<ref name="King2010">Template:Cite book</ref><ref name="ChestnutWong2014">Template:Cite book</ref><ref name="Tiziani2013">Template:Cite book</ref>

Compound	Route	Dose
Codeine	Template:Abbr	200 mg
Hydrocodone	Template:Abbr	30 mg
Hydromorphone	Template:Abbr	7.5 mg
Hydromorphone	Template:Abbr	1.5 mg
Morphine	Template:Abbr	30 mg
Morphine	Template:Abbr	10 mg
Oxycodone	Template:Abbr	20 mg
Oxycodone	Template:Abbr	10 mg
Oxymorphone	Template:Abbr	10 mg
Oxymorphone	Template:Abbr	1 mg

Hydrocodone is a highly selective full agonist of the μ-opioid receptor (MOR).<ref name="pmid21785485" /><ref name="pmid14600248">Template:Cite journal</ref><ref name="pmid7562497" /> This is the main biological target of the endogenous opioid neuropeptide β-endorphin.<ref name="TalleyFrankum2015">Template:Cite book</ref> Hydrocodone has low affinity for the δ-opioid receptor (DOR) and the κ-opioid receptor (KOR), where it is an agonist similarly.<ref name="pmid7562497" />

Studies have shown hydrocodone is stronger than codeine but only one-tenth as potent as morphine at binding to receptors and reported to be only 59% as potent as morphine in analgesic properties. However, in tests conducted on rhesus monkeys, the analgesic potency of hydrocodone was actually higher than morphine.<ref name="DavisGlare2005">Template:Cite book</ref> Oral hydrocodone has a mean equivalent daily dosage (MEDD) factor of 0.4, meaning that 1 mg of hydrocodone is equivalent to 0.4 mg of intravenous morphine. However, because of morphine's low oral bioavailability, there is a 1:1 correspondence between orally administered morphine and orally administered hydrocodone.<ref name="medd-chart">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Pharmacokinetics

Absorption

Hydrocodone is only pharmaceutically available as an oral medication.<ref name="ElliottSmith2016" /> It is well-absorbed, but the oral bioavailability of hydrocodone is only approximately 25%.<ref name="FiresteinBudd2016" /><ref name="ChabnerLongo2010" /> The onset of action of hydrocodone via this route is 10 to 20 minutes, with a peak effect (T_max) occurring at 30 to 60 minutes,<ref name="King2010" /> and it has a duration of 4 to 8 hours.<ref name="ElliottSmith2016" /> The FDA label for immediate-release hydrocodone with acetaminophen does not include any information on the influence of food on its absorption or other pharmacokinetics.<ref name="Norco-FDA-Label-2019">Hydrocodone Bitartrate and Acetaminophen Tablets, USP 5 mg/325 mg CII Template:Webarchive fda.gov</ref> Conversely, coadministration with a high-fat meal increases peak concentrations of different formulations of extended-release hydrocodone by 14 to 54%, whereas area-under-the-curve levels are not notably affected.<ref name="pmid28635354">Template:Cite journal</ref><ref name="pmid28948482">Template:Cite journal</ref><ref name="pmid25653563">Template:Cite journal</ref><ref name="pmid26614499">Template:Cite journal</ref>

Distribution

The volume of distribution of hydrocodone is 3.3 to 4.7 L/kg.<ref name="ChabnerLongo2010" /> The plasma protein binding of hydrocodone is 20 to 50%.<ref name="pmid21785485"/>

Metabolism

In the liver, hydrocodone is transformed into several metabolites, including norhydrocodone, hydromorphone, 6α-hydrocodol (dihydrocodeine), and 6β-hydrocodol.<ref name="Zhou2016">Template:Cite book</ref> 6α- and 6β-hydromorphol are also formed, and the metabolites of hydrocodone are conjugated (via glucuronidation).<ref name="FFFLM2007">Template:Cite book</ref><ref name="DasguptaSepulveda2013">Template:Cite book</ref> Hydrocodone has a terminal half-life that averages 3.8 hours (range 3.3–4.4 hours).<ref name="DavisGlare2005" /><ref name="ElliottSmith2016">Template:Cite book</ref> The hepatic cytochrome P450 enzyme CYP2D6 converts hydrocodone into hydromorphone, a more potent opioid (5-fold higher binding affinity to the MOR).<ref name="Zhou2016" /><ref name="DasguptaLangman2012" /> However, extensive and poor cytochrome 450 CYP2D6 metabolizers had similar physiological and subjective responses to hydrocodone, and CYP2D6 inhibitor quinidine did not change the responses of extensive metabolizers, suggesting that inhibition of CYP2D6 metabolism of hydrocodone has no practical importance.<ref name="pmid9103485">Template:Cite journal</ref><ref name="pmid16968950">Template:Cite journal</ref> Ultra-rapid CYP2D6 metabolizers (1–2% of the population) may have an increased response to hydrocodone; however, hydrocodone metabolism in this population has not been studied.<ref name="pmid22205192">Template:Cite journal</ref>

Norhydrocodone, the major metabolite of hydrocodone, is predominantly formed by CYP3A4-catalyzed oxidation.<ref name="Zhou2016" /> In contrast to hydromorphone, it is described as inactive.<ref name="DasguptaLangman2012">Template:Cite book</ref> However, norhydrocodone is actually a MOR agonist with similar potency to hydrocodone, but has been found to produce only minimal analgesia when administered peripherally to animals (likely due to poor blood–brain barrier and thus central nervous system penetration).<ref name="NavaniYoburn2013">Template:Cite journal</ref> Inhibition of CYP3A4 in a child who was, in addition, a poor CYP2D6 metabolizer, resulted in a fatal overdose of hydrocodone.<ref name="pmid20837591">Template:Cite journal</ref> Approximately 40% of hydrocodone metabolism is attributed to non-cytochrome P450-catalyzed reactions.<ref name="pmid23226064">Template:Cite journal</ref>

Elimination

Hydrocodone is excreted in urine, mainly in the form of conjugates.<ref name="Bluth2016" /><ref name="Smith2013" />

Chemistry

Detection in body fluids

Hydrocodone concentrations are measured in blood, plasma, and urine to seek evidence of misuse, to confirm diagnoses of poisoning, and to assist in investigations into deaths. Many commercial opiate screening tests react indiscriminately with hydrocodone, other opiates, and their metabolites, but chromatographic techniques can easily distinguish hydrocodone uniquely. Blood and plasma hydrocodone concentrations typically fall into the 5–30 μg/L range among people taking the drug therapeutically, 100–200 μg/L among recreational users, and 100–1,600 μg/L in cases of acute, fatal overdosage. Co-administration of the drug with food or alcohol can very significantly increase the resulting plasma hydrocodone concentrations that are subsequently achieved.<ref name="pmid12665006">Template:Cite journal</ref><ref name="Baselt2017">Template:Cite book</ref>

Synthesis

Hydrocodone is most commonly synthesized from thebaine, a constituent of opium latex from the dried poppy plant. Once thebaine is obtained, the reaction undergoes hydrogenation using a palladium catalyst.<ref>Template:Cite journal</ref>

Structure

There are three important structures in hydrocodone: the amine group, which binds to the tertiary nitrogen binding site in the central nervous system's opioid receptor, the hydroxy group that binds to the anionic binding site, and the phenyl group which binds to the phenolic binding site.<ref>Template:Cite book</ref> This triggers a G protein activation and subsequent release of dopamine.<ref>Template:Cite book</ref>

History

Hydrocodone was first synthesized in Germany in 1920 by Carl Mannich and Helene Löwenheim.<ref name="MannichLöwenheim1920">Template:Cite journal</ref> It was approved by the Food and Drug Administration on 23 March 1943 for sale in the United States and approved by Health Canada for sale in Canada under the brand name Hycodan.<ref name="Drugs@FDA">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="FDA">{{#invoke:citation/CS1|citation |CitationClass=web }} See section I. B., DESI Review of Hydrocodone Products</ref>

Hydrocodone was first marketed by Knoll as Dicodid, starting in February 1924 in Germany. This name is analogous to other products the company introduced or otherwise marketed: Dilaudid (hydromorphone, 1926), Dinarkon (oxycodone, 1917), Dihydrin (dihydrocodeine, 1911), and Dimorphan (dihydromorphine). Paramorfan is the trade name of dihydromorphine from another manufacturer, as is Paracodin, for dihydrocodeine.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Hydrocodone was patented in 1923, while the long-acting formulation was approved for medical use in the United States in 2013.<ref name="AHFS2019" /><ref name="Fis2006">Template:Cite book</ref> It is most commonly prescribed in the United States, which consumed 99% of the worldwide supply as of 2010.<ref>Template:Cite newsTemplate:Cbignore</ref> In 2018, it was the 402nd most commonly prescribed medication in the United States, with more than 400,000 prescriptions.<ref name="Hydrocodone - Drug Usage Statistics" />

Society and culture

Formulations

Several common imprints for hydrocodone are M365, M366, M367.<ref name="UnitedNations2009">Template:Cite bookTemplate:Dead link</ref>

Combination products

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}}

File:Hydrocodone-paracetamol-5-500.jpg

Hydrocodone and paracetamol (acetaminophen) 10-325 tablets (Mallinckrodt)

Most hydrocodone formulations include a second analgesic, such as paracetamol (acetaminophen) or ibuprofen. Examples of hydrocodone combinations include Norco, Vicodin, Vicoprofen and Riboxen.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Legal status in the United States

The US government imposed tougher prescribing rules for hydrocodone in 2014, changing the drug from Schedule III to Schedule II.<ref name="McCarthy2016">Template:Cite journal</ref><ref name="JonesLurie2016">Template:Cite journal</ref><ref name="ChambersGleason2016">Template:Cite journal</ref><ref>Template:Cite news</ref> In 2011, hydrocodone products were involved in around 100,000 abuse-related emergency department visits in the United States, more than double the number in 2004.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Veterinary use

Hydrocodone is predominantly used as an antitussive in dogs. Hydrocodone has low oral bioavailability and provide poor analgesia in cats and dogs. One study in dogs found hydrocodone to be less effective than firocoxib for dogs undergoing a tibial-plateau-levelling osteotomy.<ref>Template:Cite book</ref>

External links

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  | group2 = Semisynthetic
  | list2 =

• Acetyldihydrocodeine
• Benzylmorphine
• BuprenorphineTemplate:Nbsp(+naloxone)
• Butorphanol
• Desomorphine
• DihydrocodeineTemplate:Nbsp(+paracetamol)
• Dihydromorphine
• Etorphine
• Ethylmorphine
• HydrocodoneTemplate:Nbsp(+paracetamol, +ibuprofen, +aspirin)
• Hydromorphinol
• Hydromorphone
• Levorphanol
• Metopon
• Nalbuphine
• Nicocodeine
• Nicodicodine
• Nicomorphine
• OxycodoneTemplate:Nbsp(+paracetamol, +aspirin, +ibuprofen, +naloxone, +naltrexone)
• Oxymorphone
• Papaveretum
• Thebacon

  | group3 = Synthetic
  | list3 =

• Alfentanil
• Alphaprodine
• Anileridine
• Bezitramide
• Carfentanil
• Dextromoramide
• Dextropropoxyphene
• Dezocine
• Dimenoxadol
• Dipipanone
• Ethoheptazine
• Fentanyl^# (+fluanisone)
• Ketobemidone
• Lofentanil
• Meptazinol
• Methadone^#
• NFEPP
• Norpipanone
• Oliceridine
• Pentazocine
• Pethidine (meperidine)
• Phenadoxone
• Phenazocine
• Phenoperidine
• Piminodine
• Piritramide
• Proheptazine
• Propiram
• Remifentanil
• Sufentanil
• Tapentadol
• Tilidine
• TramadolTemplate:Nbsp(+celecoxib, +paracetamol)
• Viminol

}}

| group2 = Paracetamol-type
| list2 =

• Acetanilide^‡
• Bucetin^‡
• Butacetin^‡
• Paracetamol (acetaminophen)^#
  • +aspirin/caffeine
  • +codeine
  • +hydrocodone
  • +ibuprofen
  • +metoclopramide
  • +oxycodone
  • +propyphenazone/caffeine
  • +tramadol
• Parapropamol^‡
• Phenacetin^‡
• Propacetamol^‡

| group3 = NSAIDs
| list3 = {{#invoke:navbox|navbox|child

  | group1 = Propionates
  | list1 =

• Benoxaprofen ^‡
• Fenoprofen
• Flurbiprofen
• Ibuprofen^#Template:Nbsp(Dexibuprofen)Template:Nbsp(+paracetamol)
• KetoprofenTemplate:Nbsp(Dexketoprofen)
• Loxoprofen
• Naproxen
• Oxaprozin
• Suprofen
• Tiaprofenic acid
• Zaltoprofen

  | group2 = Oxicams
  | list2 =

• Isoxicam
• Lornoxicam
• Meloxicam
• Piroxicam
• Tenoxicam

  | group3 = Acetates
  | list3 =

• Acemetacin
• Bromfenac
• Diclofenac
• Etodolac
• IndometacinTemplate:Nbsp(Indometacin farnesil)
• Ketorolac
• Sulindac
• Tolmetin
• Zomepirac ^‡

  | group4 = COX-2 inhibitors
  | list4 =

• CelecoxibTemplate:Nbsp(+tramadol)
• Etoricoxib
• Lumiracoxib ^‡
• Parecoxib
• Rofecoxib ^‡
• Valdecoxib ^‡

  | group5 = Fenamates
  | list5 =

• Flufenamic acid
• Meclofenamic acid
• Mefenamic acid
• Tolfenamic acid

  | group6 = Salicylates
  | list6 =

• Aspirin (acetylsalicylic acid)^# (+paracetamol/caffeine)
• Aloxiprin
• Benorylate
• Carbasalate calcium
• Choline salicylate
• Diflunisal
• Dipyrocetyl
• Ethenzamide
• Guacetisal
• Imidazole salicylate
• Magnesium salicylate
• Morpholine salicylate
• Potassium salicylate
• Salicin
• Salicylamide
• Salsalate
• Sodium salicylate
• WintergreenTemplate:Nbsp(methyl salicylate)

  | group7 = Pyrazolones
  | list7 =

• Aminophenazone^‡
• Ampyrone
• Metamizole (dipyrone)
• Nifenazone
• Phenazone
• PropyphenazoneTemplate:Nbsp(+paracetamol/caffeine)

  | group8 = Others
  | list8 =

• Benzydamine
• Floctafenine
• Glafenine
• Nabumetone
• Nimesulide
• Proquazone

}}

| group4 = Cannabinoids
| list4 =

• Cannabidiol
• Cannabis
• Nabilone
• Nabiximols
• Tetrahydrocannabinol (dronabinol)

| group5 = Ion channel
modulators
| list5 = {{#invoke:navbox|navbox|child

  | group1 = Calcium blockers
  | list1 =

• Alcohol (ethanol)
• Gabapentin
• Gabapentin enacarbil
• Leconotide
• Mirogabalin
• Pregabalin
• Ziconotide

  | group2 = Sodium blockers
  | list2 =

• Carbamazepine
• Lacosamide
• Local anesthetics (e.g., cocaine, lidocaine)
• Mexiletine
• Nefopam
• Tricyclic antidepressants (e.g., amitriptyline^#)

• Na_v1.7/1.8-selective: DSP-2230^§
• Funapide^§
• PF-05089771^§
• Suzetrigine

  | group3 = Potassium openers
  | list3 =

• Flupirtine^‡

}}

| group6 = Myorelaxants
| list6 =

• Carisoprodol
• Chlorzoxazone
• Cyclobenzaprine
• Mephenoxalone
• Methocarbamol
• Orphenadrine

| group7 = Others
| list7 =

• Analgecine
• Analgesic adjuvant
• Bedinvetmab
• Camphor
• Capsaicin
• Clonidine
• Frunevetmab
• Ketamine
• Menthol
• Methoxyflurane
• Phenazopyridine
• Proglumide
• Rimazolium
• Tanezumab

| list8 =

}} Template:Cough and cold preparations Template:Opioid receptor modulators Template:Portal bar Template:Authority control