View source for Analgesic

{{Short description|Drugs used to achieve relief from pain}}
{{For|the medical condition of hereditary analgesia|Congenital insensitivity to pain}}
{{hatnote group|
{{hatnote|"Painkiller" and similar terms redirect here.}}
{{other uses|Painkiller (disambiguation)}}
}}
{{Infobox drug class
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An '''analgesic drug''', also called simply an '''analgesic''', '''antalgic''', '''pain reliever''', or '''painkiller''', is any member of the group of [[Pharmaceutical drug|drugs]] used for [[pain management]]. Analgesics are conceptually distinct from [[anesthetic]]s, which temporarily reduce, and in some instances eliminate, [[sense|sensation]], although analgesia and [[anesthesia]] are neurophysiologically overlapping and thus various drugs have both analgesic and anesthetic effects.

Analgesic choice is also determined by the type of pain: For [[neuropathic pain]], recent research has suggested that classes of drugs that are not normally considered analgesics, such as [[tricyclic antidepressants]] and [[anticonvulsant]]s may be considered as an alternative.<ref name="pmid14623723">{{cite journal | vauthors = Dworkin RH, Backonja M, Rowbotham MC, Allen RR, Argoff CR, Bennett GJ, Bushnell MC, Farrar JT, Galer BS, Haythornthwaite JA, Hewitt DJ, Loeser JD, Max MB, Saltarelli M, Schmader KE, Stein C, Thompson D, Turk DC, Wallace MS, Watkins LR, Weinstein SM | display-authors = 6 | title = Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations | journal = Archives of Neurology | volume = 60 | issue = 11 | pages = 1524–34 | date = November 2003 | pmid = 14623723 | doi = 10.1001/archneur.60.11.1524 | doi-access = free }}</ref>

Various analgesics, such as many [[nonsteroidal anti-inflammatory drug|NSAIDs]], are available [[over-the-counter drug|over the counter]] in most countries, whereas various others are [[prescription drug]]s owing to the substantial risks and high chances of [[drug overdose|overdose]], [[substance abuse|misuse]], and [[addiction]] in the absence of medical supervision.

==Etymology==

The word ''analgesic'' derives from [[Greek language|Greek]] ''an-'' ({{lang|grc|ἀν-}}, "without"), ''álgos'' ({{lang|grc|ἄλγος}}, "pain"),<ref>{{cite web| vauthors = Harper D |title=Online Etymology Dictionary: Analgesia|year=2001|url=http://www.etymonline.com/index.php?search=analgesia|access-date=December 3, 2012|url-status=live|archive-url=https://web.archive.org/web/20140303002645/http://www.etymonline.com/index.php?search=analgesia|archive-date=March 3, 2014}}</ref> and ''-ikos'' ({{lang|grc|-ικος}}, forming [[adjective]]s). Such drugs were usually known as "[[anodyne]]s" before the 20th century.{{sfnp|EB|1878}}{{sfnp|EB|1911}}

== Classification ==
Analgesics are typically classified based on their mechanism of action.<ref>{{Cite web|url=https://www.medicinescomplete.com/mc/bnf/current/PHP78520-analgesics.htm?q=Painkillers&t=search&ss=text&tot=2&p=2#_hit|title=British National Formulary: Analgesics|website=BNF online|access-date=8 June 2017}}</ref>

[[File:Tylenol.jpg|thumb|left|A bottle of [[acetaminophen]]|182x182px]]

=== Paracetamol (acetaminophen) ===
{{main|Paracetamol}}
Paracetamol, also known as acetaminophen or APAP, is a medication used to treat [[pain]] and [[fever]].<ref name="AHFS2016">{{cite web|title=Acetaminophen|url=https://www.drugs.com/monograph/acetaminophen.html|publisher=The American Society of Health-System Pharmacists|url-status=live|archive-url=https://web.archive.org/web/20160605063136/http://www.drugs.com/monograph/acetaminophen.html|archive-date=2016-06-05}}</ref> It is typically used for mild to moderate pain.<ref name="AHFS2016" /> In combination with [[opioid analgesic|opioid pain medication]], paracetamol is now used for more severe pain such as [[cancer pain]] and after surgery.<ref>{{cite book|chapter-url = http://www.sign.ac.uk/pdf/SIGN106.pdf|title = Guideline 106: Control of pain in adults with cancer|author = Scottish Intercollegiate Guidelines Network (SIGN)|publisher = National Health Service (NHS)|location = Scotland|year = 2008|isbn = 9781905813384|chapter = 6.1 and 7.1.1|url-status = live|archive-url = https://web.archive.org/web/20101220061154/http://sign.ac.uk/pdf/SIGN106.pdf|archive-date = 2010-12-20}}</ref> It is typically used either by mouth or [[rectally]] but is also available [[intravenously]].<ref name="AHFS2016" /><ref name="Hoch2014" /> Effects last between two and four hours.<ref name="Hoch2014" /> Paracetamol is classified as a mild analgesic.<ref name="Hoch2014">{{cite book | vauthors = Hochhauser D |title = Cancer and its Management |date=2014 |publisher=John Wiley & Sons |isbn=9781118468715 |page=119 |url= https://books.google.com/books?id=CXjDBAAAQBAJ&pg=PA119 |url-status=live|archive-url=https://web.archive.org/web/20170910083948/https://books.google.co.jp/books?id=CXjDBAAAQBAJ&pg=PA119|archive-date=2017-09-10|author-link=Daniel Hochhauser}}</ref> Paracetamol is generally safe at recommended doses.<ref>{{cite journal | vauthors = Russell FM, Shann F, Curtis N, Mulholland K | title = Evidence on the use of paracetamol in febrile children | journal = Bulletin of the World Health Organization | volume = 81 | issue = 5 | pages = 367–72 | date = 2003 | pmid = 12856055 | pmc = 2572451 }}</ref>

===NSAIDs===
{{main|Nonsteroidal anti-inflammatory drug}}
Nonsteroidal anti-inflammatory drugs (usually abbreviated to NSAIDs), are a [[drug class]] that groups together [[drug]]s that decrease pain<ref name="researchgate.net">{{cite journal | vauthors = Mallinson T |title=A review of ketorolac as a prehospital analgesic |journal=Journal of Paramedic Practice |date=2017 |volume=9 |issue=12 |pages=522–526 |url=https://www.researchgate.net/publication/321640488 |access-date=2 June 2018 |language=en|doi=10.12968/jpar.2017.9.12.522 |doi-access=free }}</ref> and [[antipyretic|lower fever]], and, in higher doses, decrease [[inflammation]].<ref name="Mallinson">{{cite journal | vauthors = Mallinson T |title=A review of ketorolac as a prehospital analgesic |journal=Journal of Paramedic Practice |date=2017 |volume=9 |issue=12 |pages=522–526 |url=https://www.researchgate.net/publication/321640488 |access-date=2 June 2018 |publisher=MA Healthcare |location=London |language=en |url-status=live |archive-url=https://web.archive.org/web/20180605033254/https://www.researchgate.net/publication/321640488_A_review_of_ketorolac_as_a_prehospital_analgesic |archive-date=5 June 2018 |doi=10.12968/jpar.2017.9.12.522 |doi-access=free }}</ref> The most prominent members of this group of drugs, [[aspirin]], [[ibuprofen]] and [[naproxen]], Diclofenac are all available [[Over-the-counter drug|over the counter]] in most countries.<ref name="The Physician and Sportsmedicine 2010">{{cite journal | vauthors = Warden SJ | title = Prophylactic use of NSAIDs by athletes: a risk/benefit assessment | journal = The Physician and Sportsmedicine | volume = 38 | issue = 1 | pages = 132–8 | date = April 2010 | pmid = 20424410 | doi = 10.3810/psm.2010.04.1770 | url = http://www.physsportsmed.com/index.php?article=1770 | url-status = live | s2cid = 44567896 | archive-url = https://web.archive.org/web/20101126145938/http://physsportsmed.com/index.php?article=1770 | archive-date = 2010-11-26 }}</ref>

==== COX-2 inhibitors ====
{{Main|COX-2 inhibitor}}

These drugs have been derived from NSAIDs. The [[cyclooxygenase]] enzyme inhibited by NSAIDs was discovered to have at least two different versions: COX1 and COX2. Research suggested most of the adverse effects of NSAIDs to be mediated by blocking the COX1 ([[Constitutive enzyme|constitutive]]) enzyme, with the analgesic effects being mediated by the COX2 ([[Adaptive enzyme|inducible]]) enzyme. Thus, the COX2 inhibitors were developed to inhibit only the COX2 enzyme (traditional NSAIDs block both versions in general). These drugs (such as [[rofecoxib]], [[celecoxib]], and [[etoricoxib]]) are equally effective analgesics when compared with NSAIDs, but cause less gastrointestinal hemorrhage in particular.<ref name="Conaghan2012">{{cite journal | vauthors = Conaghan PG | title = A turbulent decade for NSAIDs: update on current concepts of classification, epidemiology, comparative efficacy, and toxicity | journal = Rheumatology International | volume = 32 | issue = 6 | pages = 1491–502 | date = June 2012 | pmid = 22193214 | pmc = 3364420 | doi = 10.1007/s00296-011-2263-6 }}</ref>

After widespread adoption of the COX-2 inhibitors, it was discovered that most of the drugs in this class increase the risk of [[cardiovascular event]]s by 40% on average. This led to the withdrawal of rofecoxib and valdecoxib, and warnings on others. Etoricoxib seems relatively safe, with the risk of [[thrombotic]] events similar to that of non-coxib NSAID diclofenac.<ref name="Conaghan2012" />

=== Opioids ===
{{Main|Opioid}}

[[Morphine]], the archetypal [[opioid]], and other opioids (e.g., [[codeine]], [[oxycodone]], [[hydrocodone]], [[dihydromorphine]], [[pethidine]]) all exert a similar influence on the [[Cerebrum|cerebral]] [[opioid receptor]] system. [[Buprenorphine]] is a [[partial agonist]] of the μ-opioid receptor, and [[tramadol]] is a serotonin norepinephrine reuptake inhibitor (SNRI) with weak μ-opioid receptor agonist properties.<ref>{{cite journal | vauthors = Smith HS, Raffa RB, Pergolizzi JV, Taylor R, Tallarida RJ | title = Combining opioid and adrenergic mechanisms for chronic pain | journal = Postgraduate Medicine | volume = 126 | issue = 4 | pages = 98–114 | date = July 2014 | pmid = 25141248 | doi = 10.3810/pgm.2014.07.2788 | s2cid = 19782818 }}</ref> [[Tramadol]] is structurally closer to [[venlafaxine]] than to [[codeine]] and delivers analgesia by not only delivering "opioid-like" effects (through mild agonism of the [[mu receptor]]) but also by acting as a weak but fast-acting [[serotonin releasing agent]] and [[norepinephrine reuptake inhibitor]].<ref name="pmid1596676">{{cite journal | vauthors = Driessen B, Reimann W | title = Interaction of the central analgesic, tramadol, with the uptake and release of 5-hydroxytryptamine in the rat brain in vitro | journal = British Journal of Pharmacology | volume = 105 | issue = 1 | pages = 147–51 | date = January 1992 | pmid = 1596676 | pmc = 1908625 | doi = 10.1111/j.1476-5381.1992.tb14226.x }}</ref><ref name="pmid9389855">{{cite journal | vauthors = Bamigbade TA, Davidson C, Langford RM, Stamford JA | title = Actions of tramadol, its enantiomers and principal metabolite, O-desmethyltramadol, on serotonin (5-HT) efflux and uptake in the rat dorsal raphe nucleus | journal = British Journal of Anaesthesia | volume = 79 | issue = 3 | pages = 352–6 | date = September 1997 | pmid = 9389855 | doi = 10.1093/bja/79.3.352 | doi-access = free }}</ref><ref name="pmid9671098">{{cite journal | vauthors = Reimann W, Schneider F | title = Induction of 5-hydroxytryptamine release by tramadol, fenfluramine and reserpine | journal = European Journal of Pharmacology | volume = 349 | issue = 2–3 | pages = 199–203 | date = May 1998 | pmid = 9671098 | doi = 10.1016/S0014-2999(98)00195-2 }}</ref><ref name="pmid12354291">{{cite journal | vauthors = Gobbi M, Moia M, Pirona L, Ceglia I, Reyes-Parada M, Scorza C, Mennini T | title = p-Methylthioamphetamine and 1-(m-chlorophenyl)piperazine, two non-neurotoxic 5-HT releasers in vivo, differ from neurotoxic amphetamine derivatives in their mode of action at 5-HT nerve endings in vitro | journal = Journal of Neurochemistry | volume = 82 | issue = 6 | pages = 1435–43 | date = September 2002 | pmid = 12354291 | doi = 10.1046/j.1471-4159.2002.01073.x | hdl = 10533/173421 | s2cid = 13397864 | hdl-access = free }}</ref> [[Tapentadol]], with some structural similarities to tramadol, presents what is believed to be a novel drug working through two (and possibly three) different modes of action in the fashion of both a traditional opioid and as an SNRI. The effects of serotonin and [[norepinephrine reuptake inhibitor|norepinephrine]] on pain, while not completely understood, have had causal links established and drugs in the SNRI class are commonly used in conjunction with opioids (especially tapentadol and tramadol) with greater success in pain relief.

Dosing of all opioids may be limited by opioid toxicity (confusion, respiratory depression, [[myoclonus|myoclonic jerks]] and pinpoint pupils), seizures ([[tramadol]]), but opioid-tolerant individuals usually have higher dose ceilings than patients without tolerance.<ref>{{cite web| vauthors = Tozer A |title=Replacing Opioids: Developing drugs to treat pain|url=https://www.analyticalcannabis.com/articles/replacing-opioids-developing-drugs-to-treat-pain-289925|website=Analytical Cannabis|access-date=22 August 2017|url-status=live|archive-url=https://web.archive.org/web/20170822182648/https://www.analyticalcannabis.com/articles/replacing-opioids-developing-drugs-to-treat-pain-289925|archive-date=22 August 2017}}</ref>
Opioids, while very effective analgesics, may have some unpleasant side-effects. Patients starting morphine may experience [[nausea]] and [[vomiting]] (generally relieved by a short course of [[antiemetic]]s such as [[phenergan]]). [[Pruritus]] (itching) may require switching to a different opioid. [[Constipation]] occurs in almost all patients on opioids, and [[laxative]]s ([[lactulose]], [[macrogol]]-containing or co-danthramer) are typically co-prescribed.<ref name="oxford">Oxford Textbook of Palliative Medicine, 3rd ed. (Doyle D, Hanks G, Cherney I and Calman K, eds. Oxford University Press, 2004).</ref>

When used appropriately, opioids and other central analgesics are safe and effective; however, risks such as addiction and the body's becoming used to the drug (tolerance) can occur. The effect of tolerance means that frequent use of the drug may result in its diminished effect. When safe to do so, the dosage may need to be increased to maintain effectiveness against tolerance, which may be of particular concern regarding patients with chronic pain and requiring an analgesic over long periods. Opioid tolerance is often addressed with [[opioid rotation|opioid rotation therapy]] in which a patient is routinely switched between two or more non-cross-tolerant opioid medications in order to prevent exceeding safe dosages in the attempt to achieve an adequate analgesic effect.

Opioid tolerance should not be confused with [[opioid-induced hyperalgesia]]. The symptoms of these two conditions can appear very similar but the mechanism of action is different. Opioid-induced hyperalgesia is when exposure to opioids increases the sensation of pain ([[hyperalgesia]]) and can even make non-painful stimuli painful ([[allodynia]]).<ref>{{cite journal | vauthors = Bannister K | title = Opioid-induced hyperalgesia: where are we now? | journal = Current Opinion in Supportive and Palliative Care | volume = 9 | issue = 2 | pages = 116–21 | date = June 2015 | pmid = 25872113 | doi = 10.1097/SPC.0000000000000137 | s2cid = 13922218 }}</ref>

===Alcohol===
{{see also|Ethanol}}
Alcohol has biological, mental, and social effects which influence the consequences of using alcohol for pain.<ref name="ZaleMaisto2015">{{cite journal | vauthors = Zale EL, Maisto SA, Ditre JW | title = Interrelations between pain and alcohol: An integrative review | journal = Clinical Psychology Review | volume = 37 | pages = 57–71 | date = April 2015 | pmid = 25766100 | pmc = 4385458 | doi = 10.1016/j.cpr.2015.02.005 }}</ref> Moderate use of alcohol can lessen certain types of pain in certain circumstances.<ref name="ZaleMaisto2015" />

The majority of its analgesic effects come from antagonizing NMDA receptors, similarly to ketamine, thus decreasing the activity of the primary excitatory (signal boosting) [[neurotransmitter]], glutamate. It also functions as an analgesic to a lesser degree by increasing the activity of the primary inhibitory (signal reducing) neurotransmitter, GABA.<ref>{{cite journal | vauthors = Nagy J | title = Alcohol related changes in regulation of NMDA receptor functions | journal = Current Neuropharmacology | volume = 6 | issue = 1 | pages = 39–54 | date = March 2008 | pmid = 19305787 | pmc = 2645546 | doi = 10.2174/157015908783769662 }}</ref>

Attempting to use alcohol to treat pain has also been observed to lead to negative outcomes including excessive drinking and [[alcohol use disorder]].<ref name="ZaleMaisto2015" />

===Cannabis===
{{main|Medical cannabis}}
''Medical cannabis'', or ''medical marijuana'', refers to [[Cannabis (drug)|cannabis]] or its [[cannabinoids]] used to treat disease or improve symptoms.<ref>{{cite journal | vauthors = Murnion B | title = Medicinal cannabis | journal = Australian Prescriber | volume = 38 | issue = 6 | pages = 212–5 | date = December 2015 | pmid = 26843715 | pmc = 4674028 | doi = 10.18773/austprescr.2015.072 }}</ref><ref>{{cite web|title=What is medical marijuana?|url=https://www.drugabuse.gov/publications/drugfacts/marijuana-medicine|website=National Institute of Drug Abuse|access-date=19 April 2016|date=July 2015|quote=The term medical marijuana refers to using the whole unprocessed marijuana plant or its basic extracts to treat a disease or symptom.|url-status=live|archive-url=https://web.archive.org/web/20160417154854/https://www.drugabuse.gov/publications/drugfacts/marijuana-medicine|archive-date=17 April 2016}}</ref> There is evidence suggesting that cannabis can be used to treat [[chronic pain]] and [[muscle spasms]], with some trials indicating improved relief of neuropathic pain over opioids.<ref name="Borgelt2013">{{cite journal | vauthors = Borgelt LM, Franson KL, Nussbaum AM, Wang GS | s2cid = 8503107 | title = The pharmacologic and clinical effects of medical cannabis | journal = Pharmacotherapy | volume = 33 | issue = 2 | pages = 195–209 | date = February 2013 | pmid = 23386598 | doi = 10.1002/phar.1187 | doi-access = free }}</ref><ref name="JAMA2015">{{cite journal | vauthors = Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, Keurentjes JC, Lang S, Misso K, Ryder S, Schmidlkofer S, Westwood M, Kleijnen J | display-authors = 6 | title = Cannabinoids for Medical Use: A Systematic Review and Meta-analysis | journal = JAMA | volume = 313 | issue = 24 | pages = 2456–73 | date = 23 June 2015 | pmid = 26103030 | doi = 10.1001/jama.2015.6358 | url = http://jama.jamanetwork.com/data/journals/jama/934167/joi150059.pdf | url-status = live | archive-url = https://web.archive.org/web/20170921232733/http://jama.jamanetwork.com/data/journals/jama/934167/joi150059.pdf | archive-date = 21 September 2017 | hdl = 10757/558499 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Jensen B, Chen J, Furnish T, Wallace M | title = Medical Marijuana and Chronic Pain: a Review of Basic Science and Clinical Evidence | journal = Current Pain and Headache Reports | volume = 19 | issue = 10 | pages = 50 | date = October 2015 | pmid = 26325482 | doi = 10.1007/s11916-015-0524-x | s2cid = 9110606 }}</ref>

=== Combinations ===

Analgesics are frequently used in combination, such as the [[paracetamol]] and [[codeine]] preparations found in many non-prescription pain relievers. They can also be found in combination with vasoconstrictor drugs such as [[pseudoephedrine]] for [[Paranasal sinus|sinus]]-related preparations, or with [[antihistamine]] drugs for people with allergies.

While the use of paracetamol, aspirin, [[ibuprofen]], [[naproxen]], and other [[NSAIDS]] concurrently with weak to mid-range opiates (up to about the hydrocodone level) has been said to show beneficial synergistic effects by combating pain at multiple sites of action,<ref name="pmid34636261">{{cite journal | vauthors = Patel R, Dickenson AH | title = Neuropharmacological basis for multimodal analgesia in chronic pain | journal = Postgraduate Medicine  | volume = 134| issue = 3| pages = 245–259 | date = October 2021 | pmid = 34636261 | doi = 10.1080/00325481.2021.1985351 | s2cid = 238635838 }}</ref><ref name="pmid12148679">{{cite journal | vauthors = Mehlisch DR | title = The efficacy of combination analgesic therapy in relieving dental pain | journal = Journal of the American Dental Association | volume = 133 | issue = 7 | pages = 861–71 | date = July 2002 | pmid = 12148679 | doi = 10.14219/jada.archive.2002.0300 }}</ref> several combination analgesic products have been shown to have few efficacy benefits when compared to similar doses of their individual components. Moreover, these combination analgesics can often result in significant adverse events, including accidental overdoses, most often due to confusion that arises from the multiple (and often non-acting) components of these combinations.<ref name="nps01">{{cite journal | vauthors = Murnion B |title=Combination analgesics in adults |journal=Australian Prescriber |issue=33 |pages=113–5 |url=http://www.australianprescriber.com/magazine/33/4/113/5 |access-date=12 August 2010 |url-status=dead |archive-url=https://web.archive.org/web/20120325192249/http://www.australianprescriber.com/magazine/33/4/113/5 |archive-date=25 March 2012 }}</ref>

===Alternative medicine===
There is some evidence that some treatments using alternative medicine can relieve some types of pain more effectively than [[placebo]].<ref name="alternative medicine reviews">*{{cite journal | vauthors = Oltean H, Robbins C, van Tulder MW, Berman BM, Bombardier C, Gagnier JJ | s2cid = 4498929 | title = Herbal medicine for low-back pain | journal = The Cochrane Database of Systematic Reviews | issue = 12 | pages = CD004504 | date = December 2014 | volume = 2014 | pmid = 25536022 | doi = 10.1002/14651858.CD004504.pub4 | pmc = 7197042 }}
* {{cite journal | vauthors = Cameron M, Gagnier JJ, Chrubasik S | title = Herbal therapy for treating rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 2 | pages = CD002948 | date = February 2011 | pmid = 21328257 | doi = 10.1002/14651858.CD002948.pub2 }}
* {{cite journal | vauthors = Cui X, Trinh K, Wang YJ | title = Chinese herbal medicine for chronic neck pain due to cervical degenerative disc disease | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD006556 | date = January 2010 | volume = 2010 | pmid = 20091597 | doi = 10.1002/14651858.CD006556.pub2 | pmc = 7389878 }}</ref> The available research concludes that more research would be necessary to better understand the use of alternative medicine.<ref name="alternative medicine reviews" />

=== Other drugs ===
[[Nefopam]]—a monoamine reuptake inhibitor, and calcium and sodium channel modulator—is also approved for the treatment of moderate to severe pain in some countries.<ref>{{cite journal | vauthors = Girard P, Chauvin M, Verleye M | title = Nefopam analgesia and its role in multimodal analgesia: A review of preclinical and clinical studies | journal = Clinical and Experimental Pharmacology & Physiology | volume = 43 | issue = 1 | pages = 3–12 | date = January 2016 | pmid = 26475417 | doi = 10.1111/1440-1681.12506 | doi-access = free }}</ref>

[[Flupirtine]] is a centrally acting K<sup>+</sup> channel opener with weak [[NMDA antagonist]] properties.<ref>{{cite journal | vauthors = Kornhuber J, Bleich S, Wiltfang J, Maler M, Parsons CG | title = Flupirtine shows functional NMDA receptor antagonism by enhancing Mg2+ block via activation of voltage independent potassium channels. Rapid communication | journal = Journal of Neural Transmission | volume = 106 | issue = 9–10 | pages = 857–67 | year = 1999 | pmid = 10599868 | doi = 10.1007/s007020050206 | s2cid = 11636934 }}</ref> It was used in Europe for moderate to strong pain, as well as its [[migraine]]-treating and muscle-relaxant properties. It has no significant [[anticholinergic]] properties, and is believed to be devoid of any activity on dopamine, serotonin, or histamine receptors. It is not addictive, and tolerance usually does not develop.<ref>{{cite journal | vauthors = Klawe C, Maschke M | title = Flupirtine: pharmacology and clinical applications of a nonopioid analgesic and potentially neuroprotective compound | journal = Expert Opinion on Pharmacotherapy | volume = 10 | issue = 9 | pages = 1495–500 | date = June 2009 | pmid = 19505216 | doi = 10.1517/14656560902988528 | s2cid = 11597721 }}</ref> However, tolerance may develop in some cases.<ref>{{cite journal | vauthors = Stoessel C, Heberlein A, Hillemacher T, Bleich S, Kornhuber J | title = Positive reinforcing effects of flupirtine--two case reports | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 34 | issue = 6 | pages = 1120–1 | date = August 2010 | pmid = 20362025 | doi = 10.1016/j.pnpbp.2010.03.031 | s2cid = 19710997 }}</ref>

[[Ziconotide]], a blocker of potent [[N-type calcium channel|N-type voltage-gated calcium channels]], is administered [[intrathecally]] for the relief of severe, usually cancer-related pain.<ref>{{cite journal | vauthors = Bäckryd E | title = Do the potential benefits outweigh the risks? An update on the use of ziconotide in clinical practice | journal = European Journal of Pain | volume = 22 | issue = 7 | pages = 1193–1202 | date = August 2018 | pmid = 29635804 | doi = 10.1002/ejp.1229 | url = http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-149838 | s2cid = 4710528 }}</ref>

=== Adjuvants ===
{{Main|Analgesic adjuvant}}
Certain drugs that have been introduced for uses other than analgesics are also used in pain management. Both first-generation (such as [[amitriptyline]]) and newer [[Serotonin–norepinephrine reuptake inhibitor|antidepressants]] (such as [[duloxetine]]) are used alongside NSAIDs and opioids for pain involving nerve damage and similar problems. Other agents directly potentiate the effects of analgesics, such as using [[hydroxyzine]], [[promethazine]], [[carisoprodol]], or [[tripelennamine]] to increase the pain-killing ability of a given dose of opioid analgesic.

Adjuvant analgesics, also called atypical analgesics, include [[orphenadrine]], [[mexiletine]], [[pregabalin]], [[gabapentin]], [[cyclobenzaprine]], [[hyoscine]] (scopolamine), and other drugs possessing anticonvulsant, anticholinergic, and/or antispasmodic properties, as well as many other drugs with CNS actions. These drugs are used along with analgesics to modulate and/or modify the action of opioids when used against pain, especially of neuropathic origin.

[[Dextromethorphan]] has been noted to slow the development of and reverse tolerance to opioids, as well as to exert additional analgesia by acting upon [[NMDA]] receptors, as does [[ketamine]].<ref>{{cite journal | vauthors = Hewitt DJ | title = The use of NMDA-receptor antagonists in the treatment of chronic pain | journal = The Clinical Journal of Pain | volume = 16 | issue = 2 Suppl | pages = S73-9 | date = June 2000 | pmid = 10870744 | doi = 10.1097/00002508-200006001-00013 | s2cid = 40067641 }}</ref> Some analgesics such as [[methadone]] and [[ketobemidone]] and perhaps [[piritramide]] have intrinsic NMDA action.<ref>{{cite journal | vauthors = Elliott KJ, Brodsky M, Hyanansky A, Foley KM, Inturrisi CE | title = Dextromethorphan shows efficacy in experimental pain (nociception) and opioid tolerance | journal = Neurology | volume = 45 | issue = 12 Suppl 8 | pages = S66-8 | date = December 1995 | pmid = 8545027 | doi = 10.1212/WNL.45.12_Suppl_8.S66 | publisher = NEUROLOGY, 2005 | s2cid = 46279174 }}</ref>

The [[anticonvulsant]] [[carbamazepine]] is used to treat neuropathic pain. Similarly, the [[gabapentinoid]]s [[gabapentin]] and [[pregabalin]] are prescribed for neuropathic pain, and phenibut is available without prescription. Gabapentinoids work as α<sub>2</sub>δ-subunit blockers of [[voltage-gated calcium channel]]s, and tend to have other mechanisms of action as well. Gabapentinoids are all [[anticonvulsant]]s, which are most commonly used for neuropathic pain, as their mechanism of action tends to inhibit pain sensation originating from the nervous system.<ref>{{cite book|title=Drug Treatment in Urology|publisher=John Wiley & Sons, 2008| vauthors  = Eardley I, Whelan P, Kirby R, Schaeffer A |page=65|chapter=Drugs Used In The Treatment Of Interstitial Cystitis}}</ref>

=== Other uses ===

Topical analgesia is generally recommended to avoid systemic side-effects. Painful joints, for example, may be treated with an [[ibuprofen]]- or [[diclofenac]]-containing gel (The labeling for topical diclofenac has been updated to warn about drug-induced hepatotoxicity.<ref>[https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm193047.htm Voltaren Gel (diclofenac sodium topical gel) 1% – Hepatic Effects Labeling Changes<!-- Bot generated title -->] {{webarchive|url=https://web.archive.org/web/20140108173957/https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm193047.htm |date=2014-01-08 }}</ref>); [[capsaicin]] also is used [[topical cream|topical]]ly. [[Lidocaine]], an [[anesthetic]], and [[glucocorticoid|steroids]] may be injected into joints for longer-term pain relief. Lidocaine is also used for painful [[mouth sore]]s and to numb areas for [[dentistry|dental]] work and minor medical procedures. In February 2007 the FDA notified consumers and healthcare professionals of the potential hazards of topical anesthetics entering the bloodstream when applied in large doses to the skin without medical supervision. These topical anesthetics contain anesthetic drugs such as lidocaine, tetracaine, benzocaine, and prilocaine in a cream, ointment, or gel.<ref>[https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm054718.htm] {{webarchive|url=https://web.archive.org/web/20101019055341/https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm054718.htm|date=October 19, 2010}}</ref>

==Uses==
Topical [[nonsteroidal anti-inflammatory drugs]] provide pain relief in common conditions such as muscle sprains and overuse injuries. Since the side effects are also lesser, topical preparations could be preferred over oral medications in these conditions.<ref>{{cite journal|vauthors=Derry S, Moore RA, Gaskell H, McIntyre M, Wiffen PJ|date=June 2015|title=Topical NSAIDs for acute musculoskeletal pain in adults|journal=The Cochrane Database of Systematic Reviews|volume=6|issue=6|pages=CD007402|doi=10.1002/14651858.CD007402.pub3|pmc=6426435|pmid=26068955}}</ref>

== List of drugs with comparison ==

{| class="wikitable collapsible collapsed" style="width:100%"
|+ <big>Comparison of different analgesics</big>
|-
! Generic name (INN)
! Physicochemistry<ref name = MD>{{cite web|title=Martindale: The Complete Drug Reference|publisher=Pharmaceutical Press|work=Medicines Complete|access-date=9 April 2014|url=http://www.medicinescomplete.com/mc/martindale/current/|editor=Brayfield, A}}</ref>
! Mechanism of action<ref name = GG/>
! Routes of administration<br><ref name = GG/><ref name = AMH/><ref name = BNF/>
! style="width:100px;"| Pharmacokinetics<ref name = MD/>
! Indications<br><ref name=GG /><ref name=AMH /><ref name=BNF />
! Major safety concerns<br><ref name=GG>{{cite book | vauthors = Brunton L, Chabner B, Knollman B | title = Goodman and Gilman's The Pharmacological Basis of Therapeutics | year = 2010 | publisher = McGraw-Hill Professional | isbn = 978-0-07-162442-8 | edition = 12th | location = New York }}</ref><ref name=AMH>{{cite book |title=Australian Medicines Handbook |year=2013 |publisher=The Australian Medicines Handbook Unit Trust |isbn=978-0-9805790-9-3 |edition=2013 |location=Adelaide | veditors = Rossi S }}</ref><ref name=BNF>{{cite book |author=Joint Formulary Committee |title=British National Formulary (BNF) |year=2013 |isbn=978-0-85711-084-8 |edition=65 |location=London, UK |publisher=Pharmaceutical Press |url-access=registration |url=https://archive.org/details/bnf65britishnati0000unse }}</ref>
|-
| colspan="7" style="text-align:center;"| '''<big>[[Nonsteroidal anti-inflammatory drug]]s</big>'''
|-
| colspan="7" style="text-align:center;"| '''Unselective agents'''
|-
| [[Aceclofenac]] || Comes in betadex salt and free acid forms; practically insoluble in water, soluble in many organic solvents; degrades on contact with light; phenylacetic acid derivative. || As per [[diclofenac]]. || [[Oral administration|Oral]] (PO.) || Protein binding > 99%; half-life = 4 hours; metabolised to diclofenac (minor); excretion = urine (67%). || As per diclofenac. || As per diclofenac.
|-
| [[Acemetacin]] || Comes in free form; practically insoluble in water, soluble in certain organic solvents; degrades upon contact with light. Chemically related to [[indometacin]] || As per diclofenac. || PO. || Slightly metabolised to [[indometacin]]. || Rheumatoid arthritis, osteoarthritis and lower back pain. || As per diclofenac.
|-
| [[Amfenac]] || No available data. || As per diclofenac. || PO. || No data. || Pain and inflammation. || As diclofenac.
|-
| [[Aminophenazone]] || Related to phenylbutazone. || As per diclofenac. || PO. || Not available. || Musculoskeletal and joint disorders. || Agranulocytosis and cancer.
|-
| [[Ampiroxicam]] || Related to piroxicam. || As per diclofenac. || PO. || No data. || [[Rheumatoid arthritis]] and [[osteoarthritis]]. || Photosensitivity and other AEs typical of NSAIDs.
|-
| [[Amtolmetin guacil]] || Prodrug to [[tolmetin]]. || As per diclofenac. || PO. || No data. || As per diclofenac. || As per diclofenac.
|-
| [[Aspirin]] || Comes in free form, aluminium and lysine salt forms; fairly insoluble in water (1 in 300); highly soluble (1 in 5) in alcohol; degrades on contact with air. Salicylate. || Irreversibly inhibits [[COX-1]] and [[COX-2]]; hence inhibiting prostaglandin synthesis. || PO, IM, IV, rectal || Bioavailability = 80–100%; protein binding = 25–95% (inversely dependent on plasma concentration); half life = 2–3 hours, 15–30 hours (higher doses); excretion = 80–100%.<ref name=AMSR>{{cite web|title=Zorprin, Bayer Buffered Aspirin (aspirin) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=6 April 2014|url=http://reference.medscape.com/drug/zorprin-bayer-buffered-aspirin-343279#showall|url-status=live|archive-url=https://web.archive.org/web/20140407080151/http://reference.medscape.com/drug/zorprin-bayer-buffered-aspirin-343279#showall|archive-date=7 April 2014}}</ref> || Blood thinning; mild-to-moderate pain; fever; [[rheumatic fever]]; migraine; [[rheumatoid arthritis]]; [[Kawasaki's disease]] || GI bleeds; ulcers; [[Reye syndrome]]; nephrotoxicity; blood dyscrasias (rarely); [[Stevens–Johnson syndrome]] (uncommon/rare)
|-
| [[Azapropazone]] || Comes in free form; fairly insoluble in water and chloroform, soluble in ethanol; phenylbutazone. || As per diclofenac. || PO, rectal. || No data available. || Rheumatoid arthritis; gout; ankylosing spondylitis. || As per diclofenac.
|-
| [[Bendazac]] || Comes in free acid and lysine salt forms. Chemically related to [[indometacin]]. || As per acetametacin. || Topical, ophthalmologic. || N/A || Skin conditions (such as [[contact dermatitis]]) and [[cataract]]s. || Hepatotoxicity reported.
|-
| [[Benorilate]] || Aspirin-paracetamol ester. Practically insoluble in water, sparingly soluble in ethanol and methanol, soluble in acetone and chloroform. || As per aspirin and paracetamol. || PO. || Unavailable. || Osteoarthritis; rheumatoid arthritis; soft-tissue rheumatism; mild-moderate pain and fever. || As per aspirin and paracetamol.
|-
| [[Benzydamine]] || Comes in free acid form; freely soluble in water. || As per diclofenac. || Topical, PO, rectal, spray and vaginal. || No data available. || Musculoskeletal disorders; soft-tissue disorders; sore throat. || As per diclofenac.
|-
| [[Bromfenac]] || Comes in free acid form; phenylacetic acid derivative. || Reversible COX-1/COX-2 inhibitor. || Ophthalmologic. || N/A || Postoperative pain and inflammation. || Corneal ulceration.
|-
| [[Bufexamac]] || Comes in free acid form; practically insoluble in water, soluble in a few organic solvents; degrades upon contact with light. || Reversible COX-1/COX-2 inhibition. || Topical. || No data. || Skin disorders. || Skin conditions, such as contact dermatitis.
|-
| [[Carbasalate]]|| Comes in calcium salt form; fairly soluble in water. || Is metabolised to aspirin and urea. As per aspirin. || Oral. || No data. || Used for thromboembolic disorders. || As per diclofenac.
|-
| [[Clonixin]] || Comes in free acid and lysine salt forms. || Reversible COX-1/COX-2 inhibition. || PO, IM, IV, rectal. || No data. || Pain. || As per diclofenac.
|-
| [[Dexibuprofen]] || D-isomer of [[ibuprofen]]. Propionic acid derivative. || As per diclofenac. || PO. || Bioavailability = ?; protein binding = 99%; metabolism = hepatic via carboxylation and hydroxylation; half-life = 1.8–3.5 hours; excretion = Urine (90%).<ref>{{cite web|title=Seractil 300mg Film-Coated Tablets – Summary of Product Characteristics|work=electronic Medicines Compendium|publisher=Genus Pharmaceuticals|date=30 September 2005|access-date=7 April 2014|url=http://www.medicines.org.uk/emc/medicine/16949/SPC/Seractil+300mg+Film-Coated+Tablets/|url-status=dead|archive-url=https://web.archive.org/web/20140413145852/http://www.medicines.org.uk/emc/medicine/16949/SPC/Seractil+300mg+Film-Coated+Tablets/|archive-date=13 April 2014}}</ref> || Osteoarthritis; mild-moderate pain and menstrual pain.<ref>{{cite journal | vauthors = Derry S, Best J, Moore RA | title = Single dose oral dexibuprofen [S(+)-ibuprofen] for acute postoperative pain in adults | journal = The Cochrane Database of Systematic Reviews | volume = 10 | issue = 10 | pages = CD007550 | date = October 2013 | pmid = 24151035 | pmc = 4170892 | doi = 10.1002/14651858.CD007550.pub3 }}</ref> || As per diclofenac.
|-
| [[Diclofenac]] || Comes in sodium, potassium and diethylamine (topically used as a gel) salt forms; sparingly soluble in water but soluble in ethanol. Unstable in the presence of light and air. Indole acetic acid derivative. || Reversible COX-1/COX-2 inhibitor. || PO and topical. || Bioavailability = 50–60%; protein binding = 99–99.8%; hepatic metabolism; half-life = 1.2–2 hours; excretion = urine (50–70%), faeces (30–35%) || [[Rheumatoid arthritis]]; [[osteoarthritis]]; inflammatory pain (e.g. period pain); local pain/inflammation (as a gel); [[actinic keratoses]]; heavy menstrual bleeding || As per aspirin, except without Reye syndrome and with the following additions: [[myocardial infarction]]s, [[stroke]]s and [[hypertension]]. More prone to causing these AEs compared to the other non-selective NSAIDs.<ref name=card>{{cite web|title=Cardiovascular safety of Cox-2 inhibitors and non-selective NSAIDs |work=MHRA |date=26 July 2013 |access-date=7 April 2014 |url=http://www.mhra.gov.uk/Safetyinformation/Generalsafetyinformationandadvice/Product-specificinformationandadvice/Product-specificinformationandadvice-A-F/CardiovascularsafetyofCOX-2inhibitorsandnon-selectiveNSAIDs/ |url-status=dead |archive-url=https://web.archive.org/web/20140413144556/http://www.mhra.gov.uk/Safetyinformation/Generalsafetyinformationandadvice/Product-specificinformationandadvice/Product-specificinformationandadvice-A-F/CardiovascularsafetyofCOX-2inhibitorsandnon-selectiveNSAIDs/ |archive-date=April 13, 2014 }}</ref>
|-
| [[Diethylamine salicylate]]|| Freely soluble in water; degrades upon contact with light and iron. || As per diclofenac. || Topical. || N/A. || Rheumatic and musculoskeletal pain. || As per bufexamac.
|-
| [[Diflunisal]] || Comes in free acid and [[arginine]] salt forms; practically insoluble in water, soluble in ethanol; degrades upon contact with light. || As per diclofenac. || PO, IM, IV. || Bioavailability = 80–100%; protein binding > 99%; volume of distribution = 0.11 L/kg; hepatic metabolism; half-life = 8–12 hours; excretion = urine (90%), faeces (<5%).<ref name = MD/><ref>{{cite web|title=(diflunisal) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=7 April 2014|url=http://reference.medscape.com/drug/diflunisal-343285#showall|url-status=live|archive-url=https://web.archive.org/web/20140413144716/http://reference.medscape.com/drug/diflunisal-343285#showall|archive-date=13 April 2014}}</ref> || Pain; osteoarthritis; rheumatoid arthritis. || As per diclofenac.
|-
| [[Epirizole]] || Comes in free form. || As per diclofenac. || PO. || Not available. || [[Rheumatoid arthritis]]. || As per diclofenac.
|-
| [[Ethenzamide]] || Comes in free form; salicylate. || As per diclofenac. || PO. || Not available. || Musculoskeletal pain; fever. || As per diclofenac.
|-
| [[Etofenamate]] || Liquid; practically insoluble in water, miscible with ethyl acetate and methanol. || As per diclofenac. || Topical. || Not available. || Musculoskeletal, joint and soft-tissue disorders. || As per bufexamac.
|-
| [[Felbinac]] || Comes in free and [[diisopropanolamine]] salt forms; practically insoluble in water and ethanol, soluble in methanol. || As per diclofenac. || Topical. || N/A || Musculoskeletal pain and soft tissue injuries. || As per bufexamac.
|-
| [[Fenbufen]] || Comes as free acid; fairly insoluble in most solvents (including water); propionic acid derivative. || As per diclofenac. || PO. || Protein binding > 99%; half-life = 10–17 hours. || As per diclofenac. || As per diclofenac.
|-
| [[Fenoprofen]] || Comes in calcium salt; fairly insoluble in water and chloroform and fairly soluble in alcohol; sensitive to degradation by air. Propionic acid derivative. || As per diclofenac. || PO. || Bioavailability = ?; protein binding = 99%; hepatic metabolism; excretion = urine, faeces.<ref>{{cite web|title=Nalfon (fenoprofen) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=7 April 2014|url=http://reference.medscape.com/drug/nalfon-fenoprofen-343287#showall|url-status=live|archive-url=https://web.archive.org/web/20140413145315/http://reference.medscape.com/drug/nalfon-fenoprofen-343287#showall|archive-date=13 April 2014}}</ref> || Pain; rheumatoid arthritis and osteoarthritis. || As per diclofenac.
|-
| [[Fentiazac]] || Comes in free form and calcium salt; acetic acid derivative. || As per diclofenac. || PO. || No data. || As per diclofenac. || As per diclofenac.
|-
| [[Fepradinol]]|| Comes in free acid and hydrochloride salt forms. || As per diclofenac. || Topical. || N/A || Local inflammatory response. || As per bufexamac.
|-
| [[Feprazone]] || Comes in free acid and piperazine salt forms. Phenylbutazone. || As per diclofenac. || PO, Rectal, topical. || Not available. || As per diclofenac. || As per bufexamac (topical use) and diclofenac (PO/rectal).
|-
| [[Floctafenine]] || Comes in free acid form; anthranilic acid derivative. || As per diclofenac. || Oral. || Extensively metabolised by the liver; half-life = 8 hours; excretion = urinary and biliary. || Short-term relief from pain. || As per diclofenac.
|-
| [[Flufenamic acid]] || Comes in free acid form and aluminium salt form; anthranilic acid. || As per diclofenac. || Topical. || N/A || Soft tissue inflammation and pain. || As per bufexamac.
|-
| [[Flurbiprofen]] || Comes in sodium salt and free acid forms; fairly insoluble in water but soluble in ethanol; sensitive to degradation by air. Propionic acid derivative. || As per diclofenac. || PO, IM, IV, ophthalmologic. || Bioavailability = 96% (oral); protein binding > 99%; volume of distribution = 0.12 L/kg; excretion = urine (70%).<ref name = saudi>{{cite book | vauthors = Abdel-Aziz AA, Al-Badr AA, Hafez GA | journal = Profiles of Drug Substances, Excipients, and Related Methodology | title = Flurbiprofen | volume = 37 | pages = 113–81 | year = 2012 | pmid = 22469318 | doi = 10.1016/B978-0-12-397220-0.00004-0 | url = https://www.researchgate.net/publication/223981944 | format = PDF | series = Profiles of Drug Substances, Excipients and Related Methodology | isbn = 9780123972200 }}</ref> || Ophthalmologic: [[Vernal keratoconjunctivitis]]; postoperative ocular swelling; herpetic stromal keratitis, excimer laser photorefractive keratectomy; ocular gingivitis. Systemic use: [[rheumatoid arthritis]]; [[osteoarthritis]].<ref name = saudi/> || As per bromfenac (ophthalmologic) and diclofenac (PO/IM/IV).
|-
| [[Glucametacin]] || Indometacin derivative. || As per diclofenac. || PO. || Not available. || Musculoskeletal, joint, peri-articular and soft-tissue disorders. || As per diclofenac.
|-
| [[Ibuprofen]] || Comes in lysine salt and free acid forms; practically insoluble in water, but soluble in ethanol, [[acetone]], [[methanol]], [[dichloromethane]] and [[chloroform]]. Degrades in the presence of air. Propionic acid derivative. || As per diclofenac. || PO, IV, topical || Bioavailability = 80–100%; protein binding = 90–99%; hepatic metabolism, mostly via [[CYP2C9]] and [[CYP2C19]]-mediated oxidation; excretion = Urine (50–60%), faeces.<ref>{{cite journal | vauthors = Smith HS, Voss B | title = Pharmacokinetics of intravenous ibuprofen: implications of time of infusion in the treatment of pain and fever | journal = Drugs | volume = 72 | issue = 3 | pages = 327–37 | date = February 2012 | pmid = 22316349 | doi = 10.2165/11599230-000000000-00000 | s2cid = 207301513 }}</ref> || Pain; fever; inflammatory illness; [[rheumatoid arthritis]]; [[osteoarthritis]]; heavy menstrual bleeding; [[patent ductus arteriosus]].<ref name = AMH/><ref>{{cite journal | vauthors = Neumann R, Schulzke SM, Bührer C | title = Oral ibuprofen versus intravenous ibuprofen or intravenous indomethacin for the treatment of patent ductus arteriosus in preterm infants: a systematic review and meta-analysis | journal = Neonatology | volume = 102 | issue = 1 | pages = 9–15 | year = 2012 | pmid = 22414850 | doi = 10.1159/000335332 | s2cid = 40750585 }}</ref><ref>{{cite journal | vauthors = Johnston PG, Gillam-Krakauer M, Fuller MP, Reese J | title = Evidence-based use of indomethacin and ibuprofen in the neonatal intensive care unit | journal = Clinics in Perinatology | volume = 39 | issue = 1 | pages = 111–36 | date = March 2012 | pmid = 22341541 | pmc = 3598606 | doi = 10.1016/j.clp.2011.12.002 }}</ref> || As per diclofenac, except with lower risk of myocardial infarction, stroke and hypertension.
|-
| [[Imidazole salicylate]] || Comes in free form. Salicylate. || As per diclofenac. || PO, rectal, topical. || Not available. || Muscular and rheumatic pain. || As per bufexamac (topical use) and diclofenac (PO/rectal).
|-
| [[Indometacin]] || Comes in free acid and sodium salt forms; practically insoluble in water and most solvents; sensitive to degradation by light. Acetic acid derivative. || As per diclofenac. || PO, IV, rectal || Bioavailability = 100% (oral); protein binding = 90%; hepatic metabolism; excretion = urine (60%), faeces (33%).<ref>{{cite web|title=Arthrexin Indomethacin PRODUCT INFORMATION|work=TGA eBusiness Services|publisher=Alphapharm Pty Limited|date=14 October 2011|access-date=7 April 2014|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-04968-3|format=PDF|url-status=live|archive-url=https://web.archive.org/web/20151015201453/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-04968-3|archive-date=15 October 2015}}</ref> || [[Rheumatoid arthritis]]; [[osteoarthritis]]; [[gout]]; [[ankylosing spondylitis]]; period pain; patent ductus arteriosus.<ref name = AMH/> || As per diclofenac.
|-
| [[Isonixin]]|| Comes in free form. || As per diclofenac. || PO, rectal and topical. || Not available. || Musculoskeletal and joint disorders. || As per bufexamac (topical use) and diclofenac (PO/rectal).
|-
| [[Kebuzone]] || Comes in free and sodium salt form; phenylbutazone derivative. || As per diclofenac. || IM, PO. || Not available. || As per diclofenac. || As per diclofenac.
|-
| [[Ketoprofen]] || Comes in free acid, lysine salt, sodium salt and hydrochloride salt forms; the dex-enantiomer comes in [[trometamol]] salt form. Practically insoluble in water; freely soluble in most other solvents. Propionic acid derivative. || As per diclofenac. || PO, rectal, topical, transdermal, intravenous, intramuscular.<ref>{{cite journal | vauthors = Coaccioli S | title = Ketoprofen 2.5% gel: a clinical overview | journal = European Review for Medical and Pharmacological Sciences | volume = 15 | issue = 8 | pages = 943–9 | date = August 2011 | pmid = 21845805 }}</ref><ref>{{cite journal | vauthors = Adachi H, Ioppolo F, Paoloni M, Santilli V | title = Physical characteristics, pharmacological properties and clinical efficacy of the ketoprofen patch: a new patch formulation | journal = European Review for Medical and Pharmacological Sciences | volume = 15 | issue = 7 | pages = 823–30 | date = July 2011 | pmid = 21780552 }}</ref> || Bioavailability > 92% (oral), 70–90% (rectal); protein binding > 99%; volume of distribution = 0.1–0.2 L/kg; hepatic metabolism; half-life = 1.5–2 hours (oral), 2.2 hours (rectal), 2 hours (intravenous).<ref>{{cite journal | vauthors = Kokki H | title = Ketoprofen pharmacokinetics, efficacy, and tolerability in pediatric patients | journal = Paediatric Drugs | volume = 12 | issue = 5 | pages = 313–29 | date = October 2010 | pmid = 20799760 | doi = 10.2165/11534910-000000000-00000 | s2cid = 207298956 }}</ref><ref>{{cite journal | vauthors = Shohin IE, Kulinich JI, Ramenskaya GV, Abrahamsson B, Kopp S, Langguth P, Polli JE, Shah VP, Groot DW, Barends DM, Dressman JB | s2cid = 31263593 | display-authors = 6 | title = Biowaiver monographs for immediate-release solid oral dosage forms: ketoprofen | journal = Journal of Pharmaceutical Sciences | volume = 101 | issue = 10 | pages = 3593–603 | date = October 2012 | pmid = 22786667 | doi = 10.1002/jps.23233 }}</ref> || [[Rheumatoid arthritis]], [[osteoarthritis]] and superficial sporting injuries (topical use).<ref name = AMH/><ref>{{cite journal | vauthors = Sarzi-Puttini P, Atzeni F, Lanata L, Bagnasco M, Colombo M, Fischer F, D'Imporzano M | title = Pain and ketoprofen: what is its role in clinical practice? | journal = Reumatismo | volume = 62 | issue = 3 | pages = 172–88 | date = July–September 2010 | pmid = 21052564 | doi = 10.4081/reumatismo.2010.172 | doi-access = free | hdl = 2434/667356 | hdl-access = free }}</ref> || As per diclofenac.
|-
| [[Ketorolac]] || Comes in the [[trometamol]] salt form; highly soluble in water. Degrades in the presence of light. Acetic acid derivative. || As per diclofenac. || PO, IM, IV, intranasal, tromethamine and ophthalmologic. || Bioavailability of IM formulation = 100%; protein binding = 99%; hepatic metabolism mostly via glucoronic acid conjugation and p-hydroxylation; half-life = 5–6 hours; excretion = urine (91.4%), faeces (6.1%).<ref>{{cite web|title=NAME OF THE MEDICINE TORADOL (ketorolac trometamol)|work=TGA eBusiness Services|publisher=ROCHE PRODUCTS PTY LIMITED|date=3 February 2012|access-date=7 April 2014|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-01084-3|format=PDF|url-status=live|archive-url=https://web.archive.org/web/20151015201453/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-01084-3|archive-date=15 October 2015}}</ref> || Mild-moderate postoperative pain; acute migraine; inflammation of the eye due to cataract surgery or allergic seasonal [[conjunctivitis]]; prevention of acute pseudophakic cystoid macular oedema.<ref>{{cite journal | vauthors = McCormack PL | title = Ketorolac 0.45% ophthalmic solution | journal = Drugs & Aging | volume = 28 | issue = 7 | pages = 583–9 | date = July 2011 | pmid = 21721602 | doi = 10.2165/11207450-000000000-00000 | s2cid = 36573017 }}</ref><ref>{{cite journal | vauthors = Sinha VR, Kumar RV, Singh G | title = Ketorolac tromethamine formulations: an overview | journal = Expert Opinion on Drug Delivery | volume = 6 | issue = 9 | pages = 961–75 | date = September 2009 | pmid = 19663721 | doi = 10.1517/17425240903116006 | s2cid = 25006837 }}</ref><ref>{{cite journal | vauthors = De Oliveira GS, Agarwal D, Benzon HT | s2cid = 21022357 | title = Perioperative single dose ketorolac to prevent postoperative pain: a meta-analysis of randomized trials | journal = Anesthesia and Analgesia | volume = 114 | issue = 2 | pages = 424–33 | date = February 2012 | pmid = 21965355 | doi = 10.1213/ANE.0b013e3182334d68 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Garnock-Jones KP | title = Intranasal ketorolac: for short-term pain management | journal = Clinical Drug Investigation | volume = 32 | issue = 6 | pages = 361–71 | date = June 2012 | pmid = 22574632 | doi = 10.2165/11209240-000000000-00000 | s2cid = 41818971 }}</ref><ref>{{cite journal | vauthors = He A, Hersh EV | title = A review of intranasal ketorolac tromethamine for the short-term management of moderate to moderately severe pain that requires analgesia at the opioid level | journal = Current Medical Research and Opinion | volume = 28 | issue = 12 | pages = 1873–80 | date = December 2012 | pmid = 23098098 | doi = 10.1185/03007995.2012.744302 | s2cid = 25001604 }}</ref><ref>{{cite journal | vauthors = Taggart E, Doran S, Kokotillo A, Campbell S, Villa-Roel C, Rowe BH | title = Ketorolac in the treatment of acute migraine: a systematic review | journal = Headache | volume = 53 | issue = 2 | pages = 277–87 | date = February 2013 | pmid = 23298250 | doi = 10.1111/head.12009 | s2cid = 12843704 }}</ref><ref>{{cite journal | vauthors = Yilmaz T, Cordero-Coma M, Gallagher MJ | title = Ketorolac therapy for the prevention of acute pseudophakic cystoid macular edema: a systematic review | journal = Eye | volume = 26 | issue = 2 | pages = 252–8 | date = February 2012 | pmid = 22094296 | pmc = 3272202 | doi = 10.1038/eye.2011.296 }}</ref> || As per diclofenac.
|-
| [[Lornoxicam]] || Hydrochloride salt form used; oxicam derivative. || As per diclofenac. || PO. || Protein binding = 99%; volume of distribution = 0.2 L/kg; half-life = 3–5 hours; excretion = faeces (51%), urine (42%).<ref>{{cite journal | vauthors = Balfour JA, Fitton A, Barradell LB | title = Lornoxicam. A review of its pharmacology and therapeutic potential in the management of painful and inflammatory conditions | journal = Drugs | volume = 51 | issue = 4 | pages = 639–57 | date = April 1996 | pmid = 8706598 | doi = 10.2165/00003495-199651040-00008 | s2cid = 265522598 }}</ref><ref>{{cite journal | vauthors = Skjodt NM, Davies NM | title = Clinical pharmacokinetics of lornoxicam. A short half-life oxicam | journal = Clinical Pharmacokinetics | volume = 34 | issue = 6 | pages = 421–8 | date = June 1998 | pmid = 9646006 | doi = 10.2165/00003088-199834060-00001 | s2cid = 46662001 }}</ref> || Acute and chronic pain. || As per diclofenac.
|-
| [[Loxoprofen]] || Comes in sodium salt form. Propionic acid derivative. || As per diclofenac. || Topical. || N/A || Local inflammation and pain. || As per diclofenac.
|-
| [[Magnesium salicylate]] || Comes in free form; soluble in water and ethanol; salicylate. || As per diclofenac. || PO. || Not available. || As per diclofenac. || As per diclofenac.
|-
| [[Meclofenamic acid]] || Comes in free acid and sodium salt form, sodium salt is the form used in human medicine; practically insoluble in water (free acid) and freely soluble in water (sodium salt); sensitive to degradation by air and light. || As per diclofenac. || PO. || Protein binding > 99%; half-life = 2–4 hours; hepatically metabolised via oxidation, hydroxylation, dehalogenation and conjugation with glucuronic acid; excretion = urine, faeces (20–30%).<ref name = MD/> || Osteoarthritis; rheumatoid arthritis; mild-moderate pain; dysmenorrhoea; [[menorrhagia]]. || As per diclofenac.
|-
| [[Mefenamic acid]] || Comes in free acid form; practically insoluble in water, fairly insoluble in organic solvents; degrades on contact with air and light. Anthranilic acid derivative. || As per diclofenac. || PO. || Protein binding extensive; hepatic metabolism, mostly via [[CYP2C9]]; half-life = 2 hours; excretion = urine (66%), faeces (20–25%).<ref>{{cite web|title=PRODUCT INFORMATION PONSTAN CAPSULES (mefenamic acid)|work=TGA eBusiness Services|publisher=Pfizer Australia Pty Ltd|date=12 October 2012|access-date=7 April 2014|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-03251-3|format=PDF|url-status=live|archive-url=https://web.archive.org/web/20151015201453/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-03251-3|archive-date=15 October 2015}}</ref> || Inflammatory pain and heavy menstrual bleeding.<ref name = AMH/> || As per diclofenac.
|-
| [[Mofezolac]] || Comes in free form. || As per diclofenac. || PO. || Not available. || Musculoskeletal and joint pain. || As per diclofenac.
|-
| [[Morniflumate]] || Comes in free acid form; niflumic acid derivative. || As per diclofenac. || PO, rectal. || Not available. || Inflammatory conditions. || As per diclofenac.
|-
| [[Nabumetone]] || Comes in free acid form; practically insoluble in water, freely soluble in acetone; degrades on contact with air and light. || As per diclofenac. || PO. || Protein binding = 99%; hepatically metabolised; half-life = 24 hours; excretion = urine (80%), faeces (9%).<ref>{{cite web|title=Relafen (nabumetone) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=7 April 2014|url=http://reference.medscape.com/drug/relafen-nabumetone-343295#showall|url-status=live|archive-url=https://web.archive.org/web/20140413145106/http://reference.medscape.com/drug/relafen-nabumetone-343295#showall|archive-date=13 April 2014}}</ref> || Osteoarthritis; rheumatoid arthritis. || As per diclofenac.
|-
| [[Naproxen]] || Comes in free acid and sodium form; practically insoluble in water in free form, freely soluble in water (sodium salt), fairly soluble in most organic solvents. Degrades on contact with air and light. Propionic acid derivative. || As per diclofenac. || PO. || Bioavailability = ?; protein binding > 99.5%; volume of distribution = 10% of bodyweight; half-life = 12–15 hours; excretion = urine (95%), faeces (<3%).<ref>{{cite journal | vauthors = Todd PA, Clissold SP | s2cid = 195692083 | title = Naproxen. A reappraisal of its pharmacology, and therapeutic use in rheumatic diseases and pain states | journal = Drugs | volume = 40 | issue = 1 | pages = 91–137 | date = July 1990 | pmid = 2202585 | doi = 10.2165/00003495-199040010-00006 }}</ref> || Rheumatoid arthritis; osteoarthritis; ankylosing spondylitis; [[juvenile idiopathic arthritis]]; inflammatory pain; heavy menstrual bleeding. || As per diclofenac. less prone to causing thrombotic events compared to other non-selective NSAIDs.<ref name = card/>
|-
| [[Nepafenac]] || Comes in free form; related to amfenac. || As per diclofenac. || Ophthalmologic. || Unavailable. || Inflammation and pain following cataract surgery. || As per bromfenac.
|-
| [[Niflumic acid]] || Comes in free acid form, glycinamide and ethyl ester form; practically insoluble in water, soluble in ethanol, acetone and methanol. Nicotinic acid derivative. || As per diclofenac. || PO, rectal (ethyl ester, [[morniflumate]]). || Unavailable. || Musculoskeletal, joint and mouth inflammatory disorders. || As per diclofenac.
|-
| [[Oxaprozin]] || Comes in potassium and free acid forms; degrades upon contact with light. Propionic acid derivative. || As per diclofenac. || PO. || Bioavailability = ?; protein binding > 99.5%; volume of distribution = 0.15–0.25 L/kg; half-life = 50–60 hours; excretion = urine (65), faeces (35%).<ref>{{cite web|title=Daypro (oxaprozin) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=7 April 2014|url=http://reference.medscape.com/drug/daypro-oxaprozin-343297#showall|url-status=live|archive-url=https://web.archive.org/web/20140413143825/http://reference.medscape.com/drug/daypro-oxaprozin-343297#showall|archive-date=13 April 2014}}</ref><ref>{{cite journal | vauthors = Todd PA, Brogden RN | title = Oxaprozin. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy | journal = Drugs | volume = 32 | issue = 4 | pages = 291–312 | date = October 1986 | pmid = 3536423 | doi = 10.2165/00003495-198632040-00001 | s2cid = 195692751 }}</ref> || Osteoarthritis; rheumatoid arthritis. || As per diclofenac.
|-
| [[Oxyphenbutazone]] || Comes in free form. Phenylbutazone. || As per diclofenac. || PO, Ophthalmologic. || Unavailable. || Ophthalmologic: [[Episcleritis]]. Systemic (now seldom used due to adverse effects): ankylosing spondylitis; rheumatoid arthritis; osteoarthritis. || As per bromfenac. For systemic use haematological side effects such as aplastic anaemia; agranulocytosis; leucopenia; neutropenia; etc.
|-
| [[Phenazone]] || No data. || As per diclofenac. || PO, [[otolaryngologic]]. || Protein binding < 10%; half-life = 12 hours; hepatic metabolised; excretion = urine (primary), faeces. || Acute [[otitis media]]. || Nephrotoxicity and haematologic toxicity and other AEs typical of NSAIDs.
|-
| [[Phenylbutazone]] || Comes in free form; practically insoluble in water, freely soluble in most organic solvents; degrades upon contact with light and air. || As per diclofenac. || PO, rectal, topical. || No data available. || Ankylosing spondylitis; acute gout; osteoarthritis; rheumatoid arthritis. || Haematologic toxicity (including agranulocytosis, aplastic anaemia) and AEs typical of NSAIDs.
|-
| [[Piketoprofen]] || Comes in free form. || As per diclofenac. || Topical. || N/A. || Musculoskeletal, joint, peri-articular and soft-tissue disorders. || As per other topical NSAIDs.
|-
| [[Piroxicam]] || Comes in free acid and betadex salt forms; practically insoluble in water, slightly soluble in ethanol; degrades on contact with air and light. Enolic acid derivative. || As per diclofenac. || PO, topical. || Protein binding = 99%; extensively hepatically metabolised; half-life = 36–45 hours; excretion = urine, faeces.<ref>{{cite web|title=CHEMMART PIROXICAM CAPSULES|work=TGA eBusiness Services|publisher=Apotex Pty Ltd|access-date=7 April 2014|date=18 December 2013|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-06214-3|format=PDF|url-status=live|archive-url=https://web.archive.org/web/20151015201453/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-06214-3|archive-date=15 October 2015}}</ref><ref>{{cite journal | vauthors = Brogden RN, Heel RC, Speight TM, Avery GS | title = Piroxicam. A reappraisal of its pharmacology and therapeutic efficacy | journal = Drugs | volume = 28 | issue = 4 | pages = 292–323 | date = October 1984 | pmid = 6386426 | doi = 10.2165/00003495-199448060-00007 | s2cid = 209070732 }}</ref> || Rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and sports injuries (topical use).<ref name = AMH/> || As per diclofenac.
|-
| [[Proglumetacin]] || Comes in maleate salt form; indometacin derivative. || As per diclofenac. || PO, rectal, topical. || Not available. || Musculoskeletal and joint disorders. || As per diclofenac.
|-
| [[Proquazone]] || Comes in free form. || As per diclofenac. || PO, rectal. || Not available. || As per diclofenac. || As per diclofenac.
|-
| [[Pranoprofen]] || No data. || As per diclofenac. || PO, ophthalmologic. || Not available. || Pain, inflammation and fever. || As per diclofenac.
|-
| [[Salamidacetic acid]]|| Comes in sodium and diethylamine salt forms; salicylate. || As per diclofenac. || PO. || Unavailable. || Musculoskeletal disorders. || As per diclofenac.
|-
| [[Salicylamide]] || Fairly insoluble in water and chloroform; soluble in most other organic solvents; salicylate. || As per diclofenac. || PO, topical. || No data. || Muscular and rheumatic diseases. || As per diclofenac.
|-
| [[Salol]] || No data. || As per diclofenac. || PO, topical. || No data. || Lower urinary tract infections. || As per diclofenac.
|-
| [[Salsalate]] || Degrades upon contact with air; salicylate derivative. || As per diclofenac. || PO. || Hepatic metabolism; half-life = 7–8 hours; excretion = urine.<ref>{{cite web|title=(salsalate) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=7 April 2014|url=http://reference.medscape.com/drug/salsalate-343340#showall|url-status=live|archive-url=https://web.archive.org/web/20140413145104/http://reference.medscape.com/drug/salsalate-343340#showall|archive-date=13 April 2014}}</ref> || Rheumatoid arthritis, osteoarthritis. || As per diclofenac.
|-
| [[Sodium salicylate]] || Freely soluble in water; degrades upon contact with air and light; salicylate. || As per diclofenac. || PO, IV, topical. || No data. || Pain, fever and rheumatic conditions. || Cardiac problems; otherwise As per diclofenac.
|-
| [[Sulindac]] || Comes in free acid and sodium salt forms; practically insoluble in water and hexane, very slightly soluble in most organic solvents. Degrades upon contact with light. Acetic acid derivative. || As per diclofenac. || PO, rectal. || Bioavailability = 90%; protein binding = 93% (sulindac), 98% (active metabolite); hepatic metabolism; excretion = urine (50%), faeces (25%).<ref>{{cite web|title=Aclin Sulindac|work=TGA eBusiness Services|publisher=Alphapharm Pty Limited|date=8 November 2011|access-date=7 April 2014|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-04956-3|format=PDF|url-status=live|archive-url=https://web.archive.org/web/20151015201453/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-04956-3|archive-date=15 October 2015}}</ref> || Rheumatoid arthritis; osteoarthritis; gout; ankylosing spondylitis; inflammatory pain.<ref name = AMH/> || As per diclofenac.
|-
| [[Suxibuzone]] || Practically insoluble in water, soluble in ethanol and acetone; phenylbutazone. || As per diclofenac. || PO, topical. || No data. || Musculoskeletal and joint disorders. || As per phenylbutazone.
|-
| [[Tenoxicam]] || Comes as free acid; practically insoluble in water, fairly insoluble in organic solvents; degrades upon contact with light. || As per diclofenac. || PO, rectal. || Bioavailability = 100% (oral), 80% (rectal); protein binding = 99%; volume of distribution = 0.15 L/kg; half-life = 60–75 hours; excretion = urine (67%), faeces (33%).<ref>{{cite journal | vauthors = Gonzalez JP, Todd PA | title = Tenoxicam. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy | journal = Drugs | volume = 34 | issue = 3 | pages = 289–310 | date = September 1987 | pmid = 3315620 | doi = 10.2165/00003495-198734030-00001 | s2cid = 195698431 }}</ref> || Osteoarthritis; rheumatoid arthritis; soft tissue injury. || As per diclofenac.
|-
| [[Tetridamine]]|| No data. || As per diclofenac. || Vaginal. || No data. || [[Vaginitis]]. || As per diclofenac.
|-
| [[Tiaprofenic acid]] || Comes as free acid; practically insoluble in water but freely soluble in most organic solvents; propionic acid derivative; degrades upon contact with light. Propionic acid derivative. || As per diclofenac. || PO. || Protein binding > 99%; volume of distribution = 0.1–0.2 L/kg; hepatic metabolism; half-life = 2–4 hours.<ref>{{cite journal | vauthors = Davies NM | title = Clinical pharmacokinetics of tiaprofenic acid and its enantiomers | journal = Clinical Pharmacokinetics | volume = 31 | issue = 5 | pages = 331–47 | date = November 1996 | pmid = 9118583 | doi = 10.2165/00003088-199631050-00002 | s2cid = 25446820 }}</ref> || Ankylosing spondylitis; osteoarthritis; rheumatoid arthritis; fibrosis; capsulitis; soft-tissue disorders. || As per diclofenac.
|-
| [[Tiaramide]]|| No data. || As per diclofenac. || PO. || No data. || Pain; inflammation. || As per diclofenac.
|-
| [[Tinoridine]]|| No data. || As per diclofenac. || No data. || No data. || Pain; inflammation. || As per diclofenac.
|-
| [[Tolfenamic acid]] || Comes as free acid; practically insoluble in water; degrades upon contact with light; anthranilic acid. || As per diclofenac. || PO. || Protein binding = 99%; half-life = 2 hours; hepatically metabolised; excretion = urine (90%), faeces. || Migraine; osteoarthritis; rheumatoid arthritis; dysmenorrhoea. || As per diclofenac.
|-
| [[Tolmetin]] || Comes in sodium salt form; freely soluble in water, slightly soluble in ethanol, freely soluble in methanol. Acetic acid derivative. || As per diclofenac. || PO. || Protein binding > 99%; volume of distribution = 7–10 L; half-life = 1 hour; excretion = urine (90%).<ref>{{cite journal | vauthors = Brogden RN, Heel RC, Speight TM, Avery GS | title = Tolmetin: a review of its pharmacological properties and therapeutic efficacy in rheumatic diseases | journal = Drugs | volume = 15 | issue = 6 | pages = 429–50 | date = June 1978 | pmid = 350558 | doi = 10.2165/00003495-197815060-00002 | s2cid = 33403236 }}</ref> || Osteoarthritis; rheumatoid arthritis. || As per diclofenac.
|-
| [[Ufenamate]] || No data. || No data. || Topical. || No data. || Inflammatory skin disorders. || As per other topical NSAIDs.
|-
| colspan="7" style="text-align:center;"| '''COX-2 selective inhibitors'''
|-
| [[Celecoxib]] || Comes in free form; practically insoluble in water, fairly soluble in organic solvents. Degrades on contact with light and moisture. [[Sulfonamide]]. || Selective COX-2 inhibitor. || PO. || Protein binding = 97%; hepatic metabolism, mostly via [[CYP2C9]]; faeces (57%), urine (27%).<ref>{{cite journal | vauthors = McCormack PL | title = Celecoxib: a review of its use for symptomatic relief in the treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis | journal = Drugs | volume = 71 | issue = 18 | pages = 2457–89 | date = December 2011 | pmid = 22141388 | doi = 10.2165/11208240-000000000-00000 | s2cid = 71357689 }}</ref> || Rheumatoid arthritis; osteoarthritis; ankylosing spondylitis; pain due to dysmenorrhoea or injury. || As per non-selective NSAIDs. More prone to causing thrombotic events than most of them, however, except diclofenac.
|-
| [[Etodolac]] || Comes in free form; practically insoluble in water, freely soluble in acetone and dehydrated alcohol. Acetic acid derivative. || As per celecoxib. || PO. || Bioavailability = ?; protein binding > 99%; volume of distribution = 0.41 L/kg; half-life = 6–7 hours; excretion = urine (73%).<ref>{{cite journal | vauthors = Lynch S, Brogden RN | title = Etodolac. A preliminary review of its pharmacodynamic activity and therapeutic use | journal = Drugs | volume = 31 | issue = 4 | pages = 288–300 | date = April 1986 | pmid = 2940079 | doi = 10.2165/00003495-198631040-00002 | s2cid = 195692567 }}</ref><ref>{{cite journal | vauthors = Balfour JA, Buckley MM | title = Etodolac. A reappraisal of its pharmacology and therapeutic use in rheumatic diseases and pain states | journal = Drugs | volume = 42 | issue = 2 | pages = 274–99 | date = August 1991 | pmid = 1717225 | doi = 10.2165/00003495-199142020-00008 | s2cid = 195693229 }}</ref><ref>{{cite journal | vauthors = Brocks DR, Jamali F | title = Etodolac clinical pharmacokinetics | journal = Clinical Pharmacokinetics | volume = 26 | issue = 4 | pages = 259–74 | date = April 1994 | pmid = 8013160 | doi = 10.2165/00003088-199426040-00003 | s2cid = 43007023 }}</ref> || Rheumatoid arthritis, including juvenile idiopathic arthritis; osteoarthritis; acute pain. || As per diclofenac.
|-
| [[Etoricoxib]] || Comes in free form; [[sulfonamide]]. || As per celecoxib. || PO. || Bioavailability = 100%; protein binding = 91.4%; volume of distribution = 120 L; half-life = 22 hours; hepatic metabolism; excretion = urine (70%), faeces (20%).<ref>{{cite journal | vauthors = Takemoto JK, Reynolds JK, Remsberg CM, Vega-Villa KR, Davies NM | title = Clinical pharmacokinetic and pharmacodynamic profile of etoricoxib | journal = Clinical Pharmacokinetics | volume = 47 | issue = 11 | pages = 703–20 | year = 2008 | pmid = 18840026 | doi = 10.2165/00003088-200847110-00002 | s2cid = 11718396 }}</ref> || Acute pain; gout; osteoarthritis. || As per diclofenac.
|-
| [[Lumiracoxib]]† || Comes in free form; acetic acid derivative. || As per celecoxib. || PO. || Bioavailability = 74%; protein binding > 98%; extensive hepatic metabolism, mostly via [[CYP2C9]]; half-life = 3–6 hours; excretion = Urine (50%), faeces (50%).<ref>{{cite journal | vauthors = Bannwarth B, Bérenbaum F | title = Lumiracoxib in the management of osteoarthritis and acute pain | journal = Expert Opinion on Pharmacotherapy | volume = 8 | issue = 10 | pages = 1551–64 | date = July 2007 | pmid = 17661736 | doi = 10.1517/14656566.8.10.1551 | s2cid = 22656859 | url = https://zenodo.org/record/897825 }}</ref> || Osteoarthritis. || As above, plus hepatotoxicity.
|-
| [[Meloxicam]] || Comes in free form; fairly insoluble in water and in most organic solvents; oxicam derivative. || As per celecoxib. || PO, rectal. || Bioavailability = 89%; protein binding > 99%; volume of distribution = 0.1–0.2 L/kg; half-life = 22–24 hours; extensive hepatic metabolism; excretion = urine (45%), faeces (47%).<ref>{{cite journal | vauthors = Davies NM, Skjodt NM | title = Clinical pharmacokinetics of meloxicam. A cyclo-oxygenase-2 preferential nonsteroidal anti-inflammatory drug | journal = Clinical Pharmacokinetics | volume = 36 | issue = 2 | pages = 115–26 | date = February 1999 | pmid = 10092958 | doi = 10.2165/00003088-199936020-00003 | s2cid = 9873285 }}</ref> || Osteoarthritis; rheumatoid arthritis. || As per diclofenac.
|-
| [[Nimesulide]] || Comes in free and betadex form; practically insoluble in water and ethanol, soluble in acetone. || As per celecoxib. || PO, rectal, topical. || Unavailable. || Acute pain; dysmenorrhoea; sprains (topical); [[tendinitis]]. || As per diclofenac.
|-
| [[Parecoxib]] || Comes in sodium salt form; sulfonamide. || As per celecoxib. || IM, IV. || Plasma binding = 98%; volume of distribution = 55 L; hepatic metabolism, mostly via [[CYP2C9]], [[CYP3A4]]; half-life = 8 hours; excretion = urine (70%).<ref>{{cite web|title=PRODUCT INFORMATION DYNASTAT parecoxib (as sodium)|work=TGA eBusiness Services|publisher=Pfizer Australia Pty Ltd|date=6 February 2013|access-date=7 April 2014|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-01151-3|format=PDF|url-status=live|archive-url=https://web.archive.org/web/20151015201453/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-01151-3|archive-date=15 October 2015}}</ref> || Postoperative pain. || As per diclofenac.
|-
| [[Rofecoxib]]† || Comes in free form; sulfonamide. || As per celecoxib. || PO. || Bioavailability = 93%; protein binding = 87%; hepatic metabolism; half-life = 17 hours.<ref>{{cite journal | vauthors = Scott LJ, Lamb HM | title = Rofecoxib | journal = Drugs | volume = 58 | issue = 3 | pages = 499–505; discussion 506–7 | date = September 1999 | pmid = 10493277 | doi = 10.2165/00003495-199958030-00016 | s2cid = 219216087 }}</ref><ref>{{cite journal | vauthors = Hillson JL, Furst DE | title = Rofecoxib | journal = Expert Opinion on Pharmacotherapy | volume = 1 | issue = 5 | pages = 1053–66 | date = July 2000 | pmid = 11249495 | doi = 10.1517/14656566.1.5.1053 | s2cid = 219291177 }}</ref> || Acute pain; osteoarthritis; rheumatoid arthritis. || As per diclofenac.
|-
| [[Valdecoxib]]† || Comes in free form; sulfonamide. || As per celecoxib. || PO. || Bioavailability = 83%; protein binding = 98%; hepatic metabolism, mostly via [[CYP3A4]] and [[CYP2C9]]; half-life = 8.11 hours; excretion = urine (90%).<ref>{{cite journal | vauthors = Ormrod D, Wellington K, Wagstaff AJ | title = Valdecoxib | journal = Drugs | volume = 62 | issue = 14 | pages = 2059–71; discussion 2072–3 | year = 2002 | pmid = 12269850 | doi = 10.2165/00003495-200262140-00005 | s2cid = 250308600 }}</ref> || Pain from [[dysmenorrhoea]]; rheumatoid arthritis; osteoarthritis. || As above and also potentially fatal skin reactions (e.g. [[toxic epidermal necrolysis]]).
|-
| colspan="7" style="text-align:center;"| '''<big>[[Opioids]]</big>'''
|-
| colspan="7" style="text-align:center;"| '''Those with a morphine skeleton'''
|-
| [[Buprenorphine]] || Comes in free and hydrochloride salt forms; fairly insoluble in water, soluble in ethanol, methanol and acetone; degrades upon contact with light. || Partial agonist at the mu opioid receptor; agonist at delta opioid receptor; antagonist at kappa opioid receptor. || Sublingual, transdermal, IM, IV, intranasal, epidural, SC. || Bioavailability = 79% (sublingual); protein binding = 96%: volume of distribution = 97–187 L/kg; half-life = 20–36 hours; excretion = urine, faeces.<ref>{{cite web|title=Buprenex, Subutex (buprenorphine) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=9 April 2014|url=http://reference.medscape.com/drug/subutex-buprenorphine-343326#showall|url-status=live|archive-url=https://web.archive.org/web/20140413021718/http://reference.medscape.com/drug/subutex-buprenorphine-343326#showall|archive-date=13 April 2014}}</ref> || Opioid dependence, moderate-severe pain. || As per codeine, respiratory effects are subject to a ceiling effect.
|-
| [[Codeine]] || Comes in free form, hydrochloride salt, sulfate salt and phosphate salts; soluble in boiling water (free form), freely soluble in ethanol (free form), soluble/freely soluble in water (salt forms); sensitive to degradation by light. Methoxy analogue of morphine. || Metabolised to morphine, which activates the [[opioid receptors]]. || PO, IM, IV. || Extensive hepatic metabolism, mostly via [[CYP2D6]], to [[morphine]]; half-life = 3–4 hours; excretion = urine (86%).<ref>{{cite web|title=PRODUCT INFORMATION ACTACODE|work=TGA eBusiness Services|publisher=Aspen Pharma Pty Ltd|date=19 September 2006|access-date=8 April 2014|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-01565-3|format=PDF|url-status=live|archive-url=https://web.archive.org/web/20151015201453/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-01565-3|archive-date=15 October 2015}}</ref> || Mild-moderate pain, often in combination with [[paracetamol]] or [[ibuprofen]]. || Constipation, dependence, sedation, itching, nausea, vomiting and respiratory depression.
|-
| [[Diamorphine]] || Comes in hydrochloride salt form; freely soluble in water, soluble in alcohol; degrades upon contact with light. Diacetyl derivative of morphine. || Rapidly hydrolysed to 6-acetylmorphine and then to morphine after crossing the blood-brain barrier which in turn activates the opioid receptors in the CNS. || IM, intrathecal, intranasal, PO, IV, SC. || Extensively metabolised to morphine with 6-acetylmorphine as a possible intermediate. Mostly excreted in urine. || Severe pain (including labour pain); cough due to terminal lung cancer; angina; left ventricular failure. || As per codeine. Higher potential for abuse compared to other opioids due to its rapid penetration of the blood-brain barrier.
|-
| [[Dihydrocodeine]] || Comes in freebase, hydrochloride, phosphate, polistirex, thiocyanate, tartrate, bitartrate and hydrogen tartrate salt forms; freely soluble in water, practically insoluble in organic solvents (hydrogen tartrate salt); degrades upon contact with air and light. || Opioid receptor agonist. || IM, IV, PO, SC. || Bioavailability = 20%; extensive hepatic metabolism, partly via [[CYP2D6]] to [[dihydromorphine]] and [[CYP3A4]] to [[nordihydrocodeine]]; half-life = 3.5 –5 hours; excretion = urine. || Moderate-severe pain; usually in combination with paracetamol and/or aspirin. || As per codeine.
|-
| [[Ethylmorphine]] || Comes in freebase, hydrochloride, camphorate and camsilate salt forms; soluble in water and alcohol; degrades upon contact with light. || Opioid receptor ligand. || PO. || No data. || Cough suppressant. || As per codeine.
|-
| [[Hydrocodone]] || Comes in hydrochloride/tartrate salt form; freely soluble in water, practically insoluble in most organic solvents; degrades upon contact with light/air. || Opioid receptor ligand. || PO. || Protein binding = 19%; extensively hepatically metabolised, mostly via [[CYP3A4]], but via [[CYP2D6]] to a lesser extent to [[hydromorphone]]; half-life = 8 hours; excretion = urine.<ref>{{cite web|title=Zohydro ER (hydrocodone) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=8 April 2014|url=http://reference.medscape.com/drug/zohydro-er-hydrocodone-343312#showall|url-status=live|archive-url=https://web.archive.org/web/20140413143613/http://reference.medscape.com/drug/zohydro-er-hydrocodone-343312#showall|archive-date=13 April 2014}}</ref> || Chronic pain. || As per codeine.
|-
| [[Hydromorphone]] || Comes in hydrochloride salt form; freely soluble in water, fairly insoluble in organic solvents; degrades upon contact with light or temperatures outside 15&nbsp;°C and 35&nbsp;°C. || Opioid receptor agonist. || IM, IV, PO, SC. || Bioavailability = 50–62% (oral); protein binding = 8–19%; extensively hepatically metabolised; half-life = 2–3 hours; excretion = urine.<ref>{{cite web|title=Dilaudid, Dilaudid HP (hydromorphone) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=8 April 2014|url=http://reference.medscape.com/drug/dilaudid-hydromorphone-343313#showall|url-status=live|archive-url=https://web.archive.org/web/20140413142313/http://reference.medscape.com/drug/dilaudid-hydromorphone-343313#showall|archive-date=13 April 2014}}</ref> || Moderate-severe pain; cough. || As per codeine.
|-
| [[Morphine]] || Comes in freebase form, hydrochloride salt, sulfate salt and tartrate salt forms; soluble in water; degrades in the presence of light. || Opioid receptor agonist (μ, δ, κ). || IM, intrathecal, PO, IV, SC, rectal. || Protein binding = 35%; extensive hepatic metabolism, with some metabolism occur in the gut after oral administration; half-life = 2 hours; excretion = urine (90%). || Moderate-severe pain. || As per codeine.
|-
| [[Nicomorphine]] || Di[[nicotinic acid]] ester derivative of morphine. || As per morphine. || IM, IV, PO, rectal, SC. || No available data. || Moderate-severe pain. || As per codeine.
|-
| [[Oxycodone]] || Comes in freebase, hydrochloride and [[terephthalate]] salt forms; freely soluble in water and practically insoluble in organic solvents; degrades upon contact with air. || Opioid receptor agonist. || PO. || Bioavailability = 60–87%; protein binding = 45%; volume of distribution = 2.6 L/kg; extensively metabolised in the liver via [[CYP3A4]] and to a lesser extent via [[CYP2D6]] to [[oxymorphone]]; half-life = 2–4 hours; excretion = urine (83%).<ref>{{cite web|title=Roxicodone, OxyContin (oxycodone) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=8 April 2014|url=http://reference.medscape.com/drug/roxicodone-oxycontin-oxycodone-343321#showall|url-status=live|archive-url=https://web.archive.org/web/20140413145108/http://reference.medscape.com/drug/roxicodone-oxycontin-oxycodone-343321#showall|archive-date=13 April 2014}}</ref> || Moderate-severe pain. || As per codeine.
|-
| [[Oxymorphone]] || Comes in hydrochloride salt form; fairly soluble in water (1 in 4), practically insoluble in most organic solvents; degrades upon contact with air, light and temperatures outside 15&nbsp;°C to 30&nbsp;°C. || As per morphine. || PO, IM, SC. || Bioavailability = 10% (oral); protein binding = 10–12%; volume of distribution = 1.94–4.22 L/kg; hepatic metabolism; half-life = 7–9 hours, 9–11 hours (XR); excretion = urine, faeces.<ref>{{cite web|title=Opana, Opana ER (oxymorphone) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=8 April 2014|url=http://reference.medscape.com/drug/opana-er-oxymorphone-343322#showall|url-status=live|archive-url=https://web.archive.org/web/20140413145319/http://reference.medscape.com/drug/opana-er-oxymorphone-343322#showall|archive-date=13 April 2014}}</ref> || Postoperative analgesia/anaesthesia; moderate-severe pain. || As per codeine.
|-
| colspan="7" style="text-align:center;"| '''Morphinans'''
|-
| [[Butorphanol]] || Comes in tartrate salt form; sparingly soluble in water, insoluble in most organic solvents; degrades upon contact with air and at temperatures outside the range of 15&nbsp;°C and 30&nbsp;°C. || Kappa opioid receptor agonist; mu opioid receptor partial agonist. || IM, IV, intranasal. || Bioavailability = 60–70% (intranasal); protein binding = 80%; volume of distribution = 487 L; hepatic metabolism, mostly via hydroxylation; excretion = urine (mostly); half-life = 4.6 hours.<ref>{{cite web|title=Stadol (butorphanol) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=8 April 2014|url=http://reference.medscape.com/drug/butorphanol-343327#showall|url-status=live|archive-url=https://web.archive.org/web/20140413145317/http://reference.medscape.com/drug/butorphanol-343327#showall|archive-date=13 April 2014}}</ref> || Moderate-severe pain, including labour pain. || As above, but with a higher propensity for causing hallucinations and delusions. Respiratory depression is subject to ceiling effect.
|-
| [[Levorphanol]] || Comes in tartrate salt form; fairly insoluble in water (1 in 50) and fairly insoluble in ethanol, chloroform and ether; unstable outside of 15&nbsp;°C and 30&nbsp;°C; phenanthrene derivative. || Mu opioid; NMDA antagonist; [[serotonin-norepinephrine reuptake inhibitor|SNRI]].<ref name = supp07>{{cite journal | vauthors = Prommer E | title = Levorphanol: the forgotten opioid | journal = Supportive Care in Cancer | volume = 15 | issue = 3 | pages = 259–64 | date = March 2007 | pmid = 17039381 | doi = 10.1007/s00520-006-0146-2 | s2cid = 10916508 }}</ref> || PO, IM, IV, SC. || Protein binding = 40%; extensive first-pass metabolism; half-life = 12–16 hours, 30 hours (repeated dosing).<ref name = supp07/><ref>{{cite web|title=Levo Dromoran (levorphanol) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=9 April 2014|url=http://reference.medscape.com/drug/levorphanol-343314#showall|url-status=live|archive-url=https://web.archive.org/web/20140413141710/http://reference.medscape.com/drug/levorphanol-343314#showall|archive-date=13 April 2014}}</ref> || Acute/chronic pain. || As per codeine.
|-
| [[Nalbuphine]] || Comes primarily as its hydrochloride salt. || Full agonist at [[kappa opioid receptor]]s, partial agonist/antagonist at the [[mu opioid receptors]].<ref name = MD/> || IM, IV, SC. || Protein binding = not significant; hepatic metabolism; half-life = 5 hours; excretion = urine, faeces.<ref>{{cite web|title=Nubain (nalbuphine) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=9 April 2014|url=http://reference.medscape.com/drug/nalbuphine-343329#showall|url-status=live|archive-url=https://web.archive.org/web/20140413143332/http://reference.medscape.com/drug/nalbuphine-343329#showall|archive-date=13 April 2014}}</ref><ref>{{cite journal | vauthors = Errick JK, Heel RC | title = Nalbuphine. A preliminary review of its pharmacological properties and therapeutic efficacy | journal = Drugs | volume = 26 | issue = 3 | pages = 191–211 | date = September 1983 | pmid = 6137354 | doi = 10.2165/00003495-198326030-00002 | s2cid = 196363445 }}</ref> || Pain; anaesthesia supplement; opioid-induced pruritus. || As per codeine. Respiratory depression is subject to ceiling effect.
|-
| colspan="7" style="text-align:center;"| '''Benzomorphans'''
|-
| [[Dezocine]] || No data available. || Mixed opioid agonist-antagonist. || IM, IV. || Volume of distribution = 9–12 L/kg; half-life = 2.2–2.7 hours. || Moderate-severe pain. || As per codeine.
|-
| [[Eptazocine]] || Comes as hydrobromide salt. || As per morphine. || IM, SC. || No data. || Moderate-severe pain. || As per codeine.
|-
| [[Pentazocine]] || Comes in free, hydrochloride and lactate salt forms; fairly insoluble in water (1:30 or less), more soluble in ethanol and chloroform; degrades upon contact with air and light. || Kappa opioid receptor agonist; mu opioid receptor antagonist/partial agonist. || IM, IV, SC. || Bioavailability = 60–70%; protein binding = 60%; hepatic metabolism; half-life = 2–3 hours; excretion = urine (primary), faeces.<ref>{{cite journal | vauthors = Brogden RN, Speight TM, Avery GS | title = Pentazocine: a review of its pharmacological properties, therapeutic efficacy and dependence liability | journal = Drugs | volume = 5 | issue = 1 | pages = 6–91 | year = 1973 | pmid = 4578369 | doi = 10.2165/00003495-197305010-00002 | s2cid = 28014084 }}</ref><ref>{{cite web|title=Talwin (pentazocine) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=9 April 2014|url=http://reference.medscape.com/drug/talwin-pentazocine-343330#showall|url-status=live|archive-url=https://web.archive.org/web/20140413144718/http://reference.medscape.com/drug/talwin-pentazocine-343330#showall|archive-date=13 April 2014}}</ref> || Moderate-severe pain. || As per codeine. Respiratory effects are subject to a ceiling effect.
|-
| colspan="7" style="text-align:center;"| '''[[Phenylpiperidine]]s'''
|-
| [[Anileridine]] || Comes in free, hydrochloride and phosphate forms; fairly insoluble in water, soluble in ethanol, ether and chloroform; degrades upon contact with air and light. || Mu opioid receptor agonist. || IM, IV. || No data. || Moderate-severe pain. || As per codeine.
|-
| [[Ketobemidone]] || Comes in hydrochloride salt form; freely soluble in water, soluble in ethanol and fairly insoluble in [[dichloromethane]]. || Mu opioid; NMDA antagonist. || PO, IM, IV, rectal. || Bioavailability = 34% (oral), 44% (rectal); half-life = 2–3.5 hours.<ref>{{cite journal | vauthors = Anderson P, Arnér S, Bondesson U, Boréus LO, Hartvig P | title = Single-dose kinetics and bioavailability of ketobemidone | journal = Acta Anaesthesiologica Scandinavica. Supplementum | volume = 74 | pages = 59–62 | year = 1982 | pmid = 6124079 | doi = 10.1111/j.1399-6576.1982.tb01848.x | s2cid = 35733660 }}</ref> || Moderate-severe pain. || As per other opioids.
|-
| [[Pethidine]] || Comes in hydrochloride form; very soluble in water, sparingly soluble in ether, soluble in ethanol; degrades upon contact with air and light. || Mu opioid receptor agonist with some serotonergic effects. || IM, IV, PO, SC. || Bioavailability = 50–60%; protein binding = 65–75%; hepatic metabolism; half-life = 2.5–4 hours; excretion = urine (primarily).<ref>{{cite web|title=Demerol, Pethidine (meperidine) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=9 April 2014|url=http://reference.medscape.com/drug/demerol-meperidine-343315#showall|url-status=live|archive-url=https://web.archive.org/web/20140408215203/http://reference.medscape.com/drug/demerol-meperidine-343315#showall|archive-date=8 April 2014}}</ref><ref>{{cite journal | vauthors = Shipton E | title = Should New Zealand continue signing up to the Pethidine Protocol? | journal = The New Zealand Medical Journal | volume = 119 | issue = 1230 | pages = U1875 | date = March 2006 | pmid = 16532042 | url = http://journal.nzma.org.nz/journal/119-1230/1875/content.pdf | url-status = dead | archive-url = https://web.archive.org/web/20140408211938/http://journal.nzma.org.nz/journal/119-1230/1875/content.pdf | archive-date = April 8, 2014 }}</ref><ref>{{cite journal | vauthors = Latta KS, Ginsberg B, Barkin RL | title = Meperidine: a critical review | journal = American Journal of Therapeutics | volume = 9 | issue = 1 | pages = 53–68 | date = January–February 2002 | pmid = 11782820 | doi = 10.1097/00045391-200201000-00010 | s2cid = 23410891 }}</ref><ref>{{cite journal |title= Strategy to Eliminate Pethidine Use in Hospitals|journal=Journal of Pharmacy Practice and Research |volume=38 |issue=2 |year=2008 |pages=88–89 | vauthors = MacPherson RD, Duguid MD |doi=10.1002/j.2055-2335.2008.tb00807.x |s2cid=71812645 |doi-access=free }}</ref><ref>{{cite journal | vauthors = Mather LE, Meffin PJ | title = Clinical pharmacokinetics of pethidine | journal = Clinical Pharmacokinetics | volume = 3 | issue = 5 | pages = 352–68 | date = September–October 1978 | pmid = 359212 | doi = 10.2165/00003088-197803050-00002 | s2cid = 35402662 }}</ref> || Moderate-severe pain. || As per other opioids; and seizures, anxiety, mood changes and [[serotonin syndrome]].
|-
| colspan="7" style="text-align:center;"| '''Open-chain opioids'''
|-
| [[Dextromoramide]] || Comes in tartrate salt and free forms; soluble in water (tartrate salt). || Mu opioid. || IM, IV, PO, rectal. || No data available. || Severe pain. || As per other opioids.
|-
| [[Dextropropoxyphene]] || Comes in free form, hydrochloride and napsilate salt forms; very soluble in water (HCl), practically insoluble in water (napsilate); degrades upon contact with light and air. || Mu opioid. || PO. || Protein binding = 80%; hepatic metabolism; half-life = 6–12 hours, 30–36 hours (active metabolite). || Mild-moderate pain. || As per other opioids, plus ECG changes.
|-
| [[Dipipanone]] || Comes in hydrochloride salt form; practically insoluble in water and ether, soluble in acetone and ethanol. || Mu opioid. || PO, often in combination with [[cyclizine]]. || Half-life = 20 hours.<ref>{{cite web|title=Dipipanone 10mg + Cyclizine 30mg Tablets – Summary of Product Characteristics|date=22 August 2012|access-date=9 April 2014|url=http://www.medicines.org.uk/emc/medicine/26936/SPC/Dipipanone+10+mg+%2b+Cyclizine+30+mg+Tablets/|url-status=dead|archive-url=https://web.archive.org/web/20140413144631/http://www.medicines.org.uk/emc/medicine/26936/SPC/Dipipanone+10+mg+%2b+Cyclizine+30+mg+Tablets/|archive-date=13 April 2014}}</ref> || Moderate-severe pain. || Less sedating than morphine, otherwise as per morphine.
|-
| [[Levacetylmethadol]]† || Comes in hydrochloride salt form. || As above plus nicotinic acetylcholine receptor antagonist. || PO. || Protein binding = 80%; half-life = 2.6 days. || Opioid dependence. || As per other opioids, plus ventricular rhythm disorders.
|-
| [[Levomethadone]] || Comes in hydrochloride salt form; soluble in water and alcohol; degrades upon contact with light. || Mu opioid; NMDA antagonist. || PO. || No data. || As per methadone. || As per methadone.
|-
| [[Meptazinol]] || Comes in hydrochloride salt form; soluble in water, ethanol and methanol, fairly insoluble in acetone; unstable at temperatures greater than 25&nbsp;°C. || Mixed opioid agonist-antagonist, partial agonist at mu-1 receptor; cholinergic actions exist. || IM, IV, PO. || Bioavailability = 8.69% (oral); protein binding = 27.1%; half-life = 2 hours; excretion = urine.<ref>{{cite journal | vauthors = Holmes B, Ward A | title = Meptazinol. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy | journal = Drugs | volume = 30 | issue = 4 | pages = 285–312 | date = October 1985 | pmid = 2998723 | doi = 10.2165/00003495-198530040-00001 | s2cid = 208818234 }}</ref> || Moderate-severe pain; perioperative analgesia; [[renal colic]]. || As per pentazocine.
|-
| [[Methadone]] || Comes in hydrochloride salt form; soluble in water and ethanol; degrades upon contact with air and light and outside the temperature range of 15&nbsp;°C and 30&nbsp;°C. || Mu opioid; NMDA antagonist. || IM, IV, PO, SC. || Bioavailability = 36–100% (mean: 70–80%); protein binding = 81–97% (mean: 87%); volume of distribution = 1.9-8 L/kg (mean: 4 L/kg); hepatic metabolism, mostly via [[CYP3A4]], [[CYP2B6]] and to a lesser extent: [[CYP2C9]], [[CYP2C19]], [[CYP2D6]] & [[CYP2C8]]; half-life = 5–130 hours (mean: 20–35 hours); excretion = urine (20–50%), faeces.<ref>{{cite journal | vauthors = Lugo RA, Satterfield KL, Kern SE | title = Pharmacokinetics of methadone | journal = Journal of Pain & Palliative Care Pharmacotherapy | volume = 19 | issue = 4 | pages = 13–24 | year = 2005 | pmid = 16431829 | doi = 10.1080/J354v19n04_05 | s2cid = 29509469 }}</ref> || Opioid addiction; chronic pain. || As per other opioids, plus QT interval prolongation.
|-
| [[Piritramide]] || Comes in free or tartrate salt forms. || Mu opioid. || IM, IV, SC. || No data available. || Severe pain. || As per other opioids.
|-
| [[Tapentadol]] || Comes in free and hydrochloride salt forms. || Mu opioid and norepinephrine reuptake inhibitor. || PO. || Bioavailability = 32%; protein binding = 20%; hepatic metabolism, mostly via [[CYP2C9]], [[CYP2C19]], [[CYP2D6]]; excretion = urine (70%), faeces; half-life = 4 hours. || Moderate-severe pain. || As per other opioids; less likely to cause nausea, vomiting and constipation.
|-
| [[Tilidine]] || Comes in hydrochloride salt form; soluble in water, ethanol and dichloromethane; degrades upon contact with light. || Mu opioid metabolite, [[nortilidine]]. || PO. || No data. || Moderate-severe pain. || As per other opioids.
|-
| [[Tramadol]] || Comes in hydrochloride salt form; freely soluble in water and methanol, insoluble in acetone; degrades at temperatures less than 15&nbsp;°C and 30&nbsp;°C and upon contact with light. || Mu opioid (mostly via its active metabolite, [[O-desmethyltramadol]]) and [[serotonin-norepinephrine reuptake inhibitor|SNRI]]. || IM, IV, PO, rectal. || Bioavailability = 70–75% (oral), 100% (IM); protein binding = 20%; hepatic metabolism, via [[CYP3A4]] and [[CYP2D6]]; half-life = 6 hours; excretion = urine, faeces. || Moderate-severe pain. || As per other opioids but with less respiratory depression and constipation. Psychiatric AEs reported. Serotonin syndrome possible if used in conjunction with other serotonergics.
|-
| colspan="7" style="text-align:center;"| '''Anilidopiperidines'''
|-
| [[Alfentanil]] || Comes in hydrochloride salt form; freely soluble in ethanol, water, methanol; degrades upon contact with air and light. || Mu opioid. || Epidural, IM, IV, intrathecally. || Protein binding = 90%; volume of distribution = small; half-life = 1–2 hours; hepatic metabolism, mostly via [[CYP3A4]]; excretion = urine. || Procedural anaesthesia. || As per other opioids. Very sedating.
|-
| [[Fentanyl]] || Comes in free, hydrochloride salt, citrate salt forms; practically insoluble in water (free form), soluble in water (citrate salt form), freely soluble in ethanol and methanol; degrades outside the temperature range of 15&nbsp;°C and 30&nbsp;°C and upon contact with light. || Mu opioid. || Buccal, epidermal, IM, IV, intrathecal, intranasal, SC, sublingual. || Bioavailability = 50% (buccal), 89% (intranasal); protein binding = 80%; hepatic metabolism, mostly via [[CYP3A4]]; half-life = 219 min; excretion = urine (primary), faeces. || Moderate-severe pain (including labour pain); adjunct to anaesthesia. || As with other opioids, with less nausea, vomiting, constipation and itching and more sedation.
|-
| [[Remifentanil]] || Comes in hydrochloride salt. || Mu opioid. || IV. || Protein binding = 70%; hydrolysed by blood and tissue esterases; half-life = 20 min; excretion = urine (95%). || Anaesthesia maintenance. || As with fentanyl.
|-
| [[Sufentanil]] || Comes in free and citrate salt forms; soluble in water, ethanol and methanol; degrades upon contact with light and temperatures outside 15&nbsp;°C and 30&nbsp;°C. || Mu opioid. || Epidural, IV, intrathecal, transdermal. || Protein binding = 90%; half-life = 2.5 hours; excretion = urine (80%). || Adjunct to anaesthesia and moderate-severe pain. || As with fentanyl.
|-
| colspan="7" style="text-align:center;"| '''<big>Other analgesics</big>'''
|-
| [[Acetanilide]] || No data. || Paracetamol prodrug. || PO. || No data. || Pain; fever. || Cancer; AEs of paracetamol.
|-
| [[Amitriptyline]] || Comes in free form and in hydrochloride and embonate salt forms; practically insoluble in water (embonate salt), freely soluble in water (HCl); degrades upon contact with light. || SNRI. || PO. || Hepatic metabolism, via [[CYP2C19]], [[CYP3A4]]; active metabolite, nortriptyline; half-life = 9–27 hours; excretion = urine (18%), faeces. || Neuropathic pain; nocturnal enuresis; major depression; migraine prophylaxis; urinary urge incontinence. || Sedation, anticholinergic effects, weight gain, orthostatic hypotension, [[sinus tachycardia]], sexual dysfunction, tremor, dizziness, sweating, agitation, insomnia, anxiety, confusion.
|-
| [[Dronabinol]] || Comes in free form; degrades upon contact with light. || Cannabinoid receptor partial agonist. || PO. || Bioavailability = 10–20%; protein binding = 90–99%; volume of distribution = 10 L/kg; hepatic metabolism; half-life = 25–36 hours, 44–59 hours (metabolites); excretion = faeces (50%), urine (15%).<ref>{{cite web|title=Marinol (dronabinol) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=9 April 2014|url=http://reference.medscape.com/drug/marinol-thc-dronabinol-342047#showall|url-status=live|archive-url=https://web.archive.org/web/20140413143823/http://reference.medscape.com/drug/marinol-thc-dronabinol-342047#showall|archive-date=13 April 2014}}</ref> || Refractory chemotherapy-induced nausea and vomiting; anorexia; neuropathic pain. || Dizziness, euphoria, paranoia, somnolence, abnormal thinking, abdominal pain, nausea, vomiting, depression, hallucinations, hypotension, special difficulties, emotional lability, tremors, flushing, etc.
|-
| [[Duloxetine]] || Comes in hydrochloride salt form; slightly soluble in water, freely soluble in methanol; degrades upon contact with light. || SNRI. || PO. || Protein binding > 90%; volume of distribution = 3.4 L/kg; hepatic metabolism, via [[CYP2D6]], [[CYP1A2]]; half-life = 12 hours; excretion = urine (70%), faeces (20%).<ref>{{cite web|title=Cymbalta (duloxetine) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=9 April 2014|url=http://reference.medscape.com/drug/cymbalta-duloxetine-342960#showall|url-status=live|archive-url=https://web.archive.org/web/20140413144908/http://reference.medscape.com/drug/cymbalta-duloxetine-342960#showall|archive-date=13 April 2014}}</ref> || Major depression; generalised anxiety disorder; neuropathic pain. || Anticholinergic effects, GI effects, yawning, sweating, dizziness, weakness, sexual dysfunction, somnolence, insomnia, headache, tremor, decreased appetite.
|-
| [[Flupirtine]] || Comes as maleate salt. Chemically related to [[retigabine]]. || Potassium channel (Kv7) opener.<ref>{{cite journal | vauthors = Szelenyi I | title = Flupirtine, a re-discovered drug, revisited | journal = Inflammation Research | volume = 62 | issue = 3 | pages = 251–8 | date = March 2013 | pmid = 23322112 | doi = 10.1007/s00011-013-0592-5 | s2cid = 16535456 }}</ref> || PO, rectal. || Bioavailability = 90% (oral), 72.5% (rectal); protein binding = 80%; volume of distribution = 154 L; hepatic metabolism; half-life = 6.5 hours; excretion = urine (72%). || Pain; [[fibromyalgia]]; [[Creutzfeldt–Jakob disease]]. || Drowsiness, dizziness, heartburn, dry mouth, fatigue and nausea.<ref>{{cite journal | vauthors = Devulder J | title = Flupirtine in pain management: pharmacological properties and clinical use | journal = CNS Drugs | volume = 24 | issue = 10 | pages = 867–81 | date = October 2010 | pmid = 20839897 | doi = 10.2165/11536230-000000000-00000 | s2cid = 22053483 }}</ref>
|-
| [[Gabapentin]] || Comes in free and enacarbil salt forms; fairly insoluble in ethanol, dichoromethane, fairly soluble in water. || Binds to the α2δ-1 subunit of voltage gated calcium ion channels in the spinal cord. May also modulate NMDA receptors and protein kinase C. || PO. || Half-life = 5–7 hours. || Neuropathic pain; epilepsy. || Fatigue, sedation, dizziness, ataxia, tremor, diplopia, nystagmus, amblyopia, amnesia, abnormal thinking, hypertension, vasodilation, peripheral oedema, dry mouth, weight gain and rash.
|-
| [[Milnacipran]] || No data. || SNRI. || PO. || Bioavailability = 85–90%; protein binding = 13%: volume of distribution = 400 L; hepatic metabolism; half-life = 6–8 hours (L-isomer), 8–10 hours (D-isomer); excretion = urine (55%).<ref>{{cite web|title=Savella (milnacipran) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=9 April 2014|url=http://reference.medscape.com/drug/savella-milnacipran-345054#showall|url-status=live|archive-url=https://web.archive.org/web/20140413144234/http://reference.medscape.com/drug/savella-milnacipran-345054#showall|archive-date=13 April 2014}}</ref> || [[Fibromyalgia]]. || As per duloxetine, plus hypertension.
|-
| [[Nabiximols]] || Contains [[cannabidiol]] and [[dronabinol]] in roughly equal concentrations. || As per dronabinol. || Buccal spray. || Not available. || Neuropathic pain and spasticity as part of [[Multiple sclerosis|MS]]. || As per dronabinol.
|-
| [[Nefopam]] || Comes in a hydrochloride salt form. Chemically related to [[orphenadrine]]. || Unknown; [[serotonin-norepinephrine-dopamine reuptake inhibitor]]. || PO, IM. || Protein binding = 73%; half-life = 4 hours; excretion = urine, faeces (8%). || Analgesia, especially postoperative; [[hiccups]]. || Has antimuscarinic and sympathomimetic effects.<ref>{{cite journal | vauthors = Evans MS, Lysakowski C, Tramèr MR | title = Nefopam for the prevention of postoperative pain: quantitative systematic review | journal = British Journal of Anaesthesia | volume = 101 | issue = 5 | pages = 610–7 | date = November 2008 | pmid = 18796441 | doi = 10.1093/bja/aen267 | doi-access = free }}</ref>
|-
| [[Paracetamol]] || Comes in free form; practically insoluble in water, freely soluble in ethanol; degrades upon contact with moisture, air and light. || Multiple; inhibits prostaglandin synthesis in the CNS, an active metabolite, [[AM404]], is an [[anandamide]] reuptake inhibitor. || PO, IV, IM, rectal. || Protein binding = 10–25%; volume of distribution = 1 L/kg; hepatic metabolism; half-life = 1–3 hours; excretion = urine.<ref>{{cite web|title=Tylenol, Tylenol Infants' Drops (acetaminophen) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=8 April 2014|url=http://reference.medscape.com/drug/tylenol-acetaminophen-343346#showall|url-status=live|archive-url=https://web.archive.org/web/20140414025534/http://reference.medscape.com/drug/tylenol-acetaminophen-343346#showall|archive-date=14 April 2014}}</ref> || Analgesia and fever reduction. || Hepatotoxicity; hypersensitivity reactions (rare), including [[Stevens–Johnson syndrome]]; hypotension (rare; IV).
|-
| [[Phenacetin]] || No data. || Prodrug to paracetamol. || PO. || No data. || Analgesia and fever reduction. || Haematologic, nephrotoxicity, cancer and paracetamol AEs.
|-
| [[Pregabalin]] || Comes in free form. || As per gabapentin. || PO. || Bioavailability = 90%; half-life = 6.3 hours; hepatic metabolism; excretion = urine (90%).<ref>{{cite journal | vauthors = McKeage K, Keam SJ | s2cid = 39007929 | title = Pregabalin: in the treatment of postherpetic neuralgia | journal = Drugs & Aging | volume = 26 | issue = 10 | pages = 883–92 | year = 2009 | pmid = 19761281 | doi = 10.2165/11203750-000000000-00000 }}</ref> || Neuropathic pain; anxiety; epilepsy. || As per gabapentin.
|-
| [[Propacetamol]] || Freely soluble in water; degrades upon contact with moisture. || Prodrug to paracetamol. || IM, IV. || No data available. || Analgesia and fever reduction. || As per paracetamol.
|-
| [[Ziconotide]] || Peptide. || N-type calcium-channel blocker. || Intrathecal. || Protein binding = 50%; half-life = 2.9–6.5 hours; excretion = urine (<1%).<ref name=ZMSR>{{cite web|title=Prialt (ziconotide) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=8 April 2014|url=http://reference.medscape.com/drug/prialt-ziconotide-343378#showall|url-status=live|archive-url=https://web.archive.org/web/20140413144504/http://reference.medscape.com/drug/prialt-ziconotide-343378#showall|archive-date=13 April 2014}}</ref> || Chronic pain. || CNS toxicity (abnormal gait, abnormal vision, memory problems, etc.); GI effects.<ref name = ZMSR/>
|-
| colspan=7 style="font-size:88%" | Where † indicates products that are no longer marketed.
|}

==Research==
Some novel and investigational analgesics include subtype-selective [[voltage-gated sodium channel]] [[sodium channel blocker|blocker]]s such as [[funapide]] and [[raxatrigine]], as well as multimodal agents such as [[ralfinamide]].<ref>{{cite journal | vauthors = Yekkirala AS, Roberson DP, Bean BP, Woolf CJ | title = Breaking barriers to novel analgesic drug development | journal = Nature Reviews. Drug Discovery | volume = 16 | issue = 8 | pages = 545–564 | date = August 2017 | pmid = 28596533 | pmc = 5675565 | doi = 10.1038/nrd.2017.87 }}</ref>

== See also ==
* [[Audioanalgesia]]
* [[Electroanalgesia]]
* [[Pain management]]
* [[Patient-controlled analgesia]]
* [[Pain in babies]]
* [[Congenital insensitivity to pain|Congenital analgesia]] (insensitivity to pain)

== References ==
=== Citations ===
{{Reflist}}

=== Sources ===
{{refbegin}}
* {{cite EB9 |mode=cs2 |wstitle=Anodyne |volume=2  |ref={{harvid|EB|1878}} |page=90 }}.
* {{cite EB1911 |mode=cs2 |wstitle=Anodyne |volume=2 |ref={{harvid|EB|1911}} |page=79 }}.
{{refend}}

{{-}}
{{Analgesics}}
{{Pain}}
{{Major Drug Groups}}

{{Authority control}}

[[Category:Pain]]
[[Category:Opioids]]
[[Category:Agnosia]]
[[Category:Analgesics| ]]