Biology:Analgesic

From HandWiki
Short description: Any member of the group of drugs used to achieve analgesia, relief from pain
Analgesic
Drug class
Opium pod cut to demonstrate fluid extraction1.jpg
Opium poppies such as this one provide ingredients for the class of analgesics called opiates.
Class identifiers
UsePain
ATC codeN02A
Clinical data
Drugs.comDrug Classes
Consumer ReportsBest Buy Drugs
WebMDMedicineNet 

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

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 anticonvulsants may be considered as an alternative.[1]

Various analgesics, such as many NSAIDs, are available over the counter in most countries, whereas various others are prescription drugs owing to the substantial risks and high chances of overdose, misuse, and addiction in the absence of medical supervision.

Etymology

The word analgesic derives from Greek an- (ἀν-, "without"), álgos (ἄλγος, "pain"),[2] and -ikos (-ικος, forming adjectives). Such drugs were usually known as "anodynes" before the 20th century.[3][4]

Classification

Analgesics are typically classified based on their mechanism of action.[5]

A bottle of acetaminophen

Paracetamol (acetaminophen)

Main page: Chemistry:Paracetamol

Paracetamol, also known as acetaminophen or APAP, is a medication used to treat pain and fever.[6] It is typically used for mild to moderate pain.[6] In combination with opioid pain medication, paracetamol is now used for more severe pain such as cancer pain and after surgery.[7] It is typically used either by mouth or rectally but is also available intravenously.[6][8] Effects last between two and four hours.[8] Paracetamol is classified as a mild analgesic.[8] Paracetamol is generally safe at recommended doses.[9]

NSAIDs

Main page: Chemistry:Nonsteroidal anti-inflammatory drug

Nonsteroidal anti-inflammatory drugs (usually abbreviated to NSAIDs), are a drug class that groups together drugs that decrease pain[10] and lower fever, and, in higher doses, decrease inflammation.[11] The most prominent members of this group of drugs, aspirin, ibuprofen and naproxen, are all available over the counter in most countries.[12]

COX-2 inhibitors

Main page: Biology: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, with the analgesic effects being mediated by the COX2 (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.[13]

After widespread adoption of the COX-2 inhibitors, it was discovered that most of the drugs in this class increase the risk of cardiovascular events 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.[13]

Opioids

Main page: Chemistry:Opioid

Morphine, the archetypal opioid, and other opioids (e.g., codeine, oxycodone, hydrocodone, dihydromorphine, pethidine) all exert a similar influence on the 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.[14] 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.[15][16][17][18] 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 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, myoclonic jerks and pinpoint pupils), seizures (tramadol), but opioid-tolerant individuals usually have higher dose ceilings than patients without tolerance.[19] 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 antiemetics such as phenergan). Pruritus (itching) may require switching to a different opioid. Constipation occurs in almost all patients on opioids, and laxatives (lactulose, macrogol-containing or co-danthramer) are typically co-prescribed.[20]

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 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).[21]

Alcohol

Alcohol has biological, mental, and social effects which influence the consequences of using alcohol for pain.[22] Moderate use of alcohol can lessen certain types of pain in certain circumstances.[22]

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.[23]

Attempting to use alcohol to treat pain has also been observed to lead to negative outcomes including excessive drinking and alcohol use disorder.[22]

Cannabis

Main page: Medicine:Medical cannabis

Medical cannabis, or medical marijuana, refers to cannabis or its cannabinoids used to treat disease or improve symptoms.[24][25] 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.[26][27][28]

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 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,[29][30] 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.[31]

Alternative medicine

There is some evidence that some treatments using alternative medicine can relieve some types of pain more effectively than placebo.[32] The available research concludes that more research would be necessary to better understand the use of alternative medicine.[32]

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.[33]

Flupirtine is a centrally acting K+ channel opener with weak NMDA antagonist properties.[34] 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.[35] However, tolerance may develop in some cases.[36]

Ziconotide, a blocker of potent N‐type voltage‐gated calcium channels, is administered intrathecally for the relief of severe, usually cancer-related pain.[37]

Adjuvants

Main page: Biology: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 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.[38] Some analgesics such as methadone and ketobemidone and perhaps piritramide have intrinsic NMDA action.[39]

High-alcohol liquor, two forms of which were found in the US Pharmacopoeia up until 1916 and in common use by physicians well into the 1930s, has been used in the past as an agent for dulling pain, due to the CNS depressant effects of ethyl alcohol, a notable example being the American Civil War.[40][better source needed] However, the ability of alcohol to relieve severe pain is likely inferior to many analgesics used today (e.g., morphine, codeine). As such, in general, the idea of alcohol for analgesia is considered a primitive practice in virtually all industrialized countries today.

The anticonvulsant carbamazepine is used to treat neuropathic pain. Similarly, the gabapentinoids gabapentin and pregabalin are prescribed for neuropathic pain, and phenibut is available without prescription. Gabapentinoids work as α2δ-subunit blockers of voltage-gated calcium channels, and tend to have other mechanisms of action as well. Gabapentinoids are all anticonvulsants, which are most commonly used for neuropathic pain, as their mechanism of action tends to inhibit pain sensation originating from the nervous system.[41]

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.[42]); capsaicin also is used topically. Lidocaine, an anesthetic, and steroids may be injected into joints for longer-term pain relief. Lidocaine is also used for painful mouth sores and to numb areas for 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.[43]

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.[44]

List of drugs with comparison


Research

Some novel and investigational analgesics include subtype-selective voltage-gated sodium channel blockers such as funapide and raxatrigine, as well as multimodal agents such as ralfinamide.[129]

See also

References

Citations

  1. "Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations". Archives of Neurology 60 (11): 1524–34. November 2003. doi:10.1001/archneur.60.11.1524. PMID 14623723. 
  2. "Online Etymology Dictionary: Analgesia". 2001. http://www.etymonline.com/index.php?search=analgesia. 
  3. EB (1878).
  4. EB (1911).
  5. "British National Formulary: Analgesics". https://www.medicinescomplete.com/mc/bnf/current/PHP78520-analgesics.htm?q=Painkillers&t=search&ss=text&tot=2&p=2#_hit. 
  6. 6.0 6.1 6.2 "Acetaminophen". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/acetaminophen.html. 
  7. Scottish Intercollegiate Guidelines Network (SIGN) (2008). "6.1 and 7.1.1". Guideline 106: Control of pain in adults with cancer. Scotland: National Health Service (NHS). ISBN 9781905813384. http://www.sign.ac.uk/pdf/SIGN106.pdf. 
  8. 8.0 8.1 8.2 Cancer and its Management. John Wiley & Sons. 2014. p. 119. ISBN 9781118468715. https://books.google.com/books?id=CXjDBAAAQBAJ&pg=PA119. 
  9. "Evidence on the use of paracetamol in febrile children". Bulletin of the World Health Organization 81 (5): 367–72. 2003. PMID 12856055. 
  10. "A review of ketorolac as a prehospital analgesic" (in en). Journal of Paramedic Practice 9 (12): 522–526. 2017. doi:10.12968/jpar.2017.9.12.522. https://www.researchgate.net/publication/321640488. Retrieved 2 June 2018. 
  11. "A review of ketorolac as a prehospital analgesic" (in en). Journal of Paramedic Practice (London: MA Healthcare) 9 (12): 522–526. 2017. doi:10.12968/jpar.2017.9.12.522. https://www.researchgate.net/publication/321640488. Retrieved 2 June 2018. 
  12. "Prophylactic use of NSAIDs by athletes: a risk/benefit assessment". The Physician and Sportsmedicine 38 (1): 132–8. April 2010. doi:10.3810/psm.2010.04.1770. PMID 20424410. http://www.physsportsmed.com/index.php?article=1770. 
  13. 13.0 13.1 "A turbulent decade for NSAIDs: update on current concepts of classification, epidemiology, comparative efficacy, and toxicity". Rheumatology International 32 (6): 1491–502. June 2012. doi:10.1007/s00296-011-2263-6. PMID 22193214. 
  14. "Combining opioid and adrenergic mechanisms for chronic pain". Postgraduate Medicine 126 (4): 98–114. July 2014. doi:10.3810/pgm.2014.07.2788. PMID 25141248. 
  15. "Interaction of the central analgesic, tramadol, with the uptake and release of 5-hydroxytryptamine in the rat brain in vitro". British Journal of Pharmacology 105 (1): 147–51. January 1992. doi:10.1111/j.1476-5381.1992.tb14226.x. PMID 1596676. 
  16. "Actions of tramadol, its enantiomers and principal metabolite, O-desmethyltramadol, on serotonin (5-HT) efflux and uptake in the rat dorsal raphe nucleus". British Journal of Anaesthesia 79 (3): 352–6. September 1997. doi:10.1093/bja/79.3.352. PMID 9389855. 
  17. "Induction of 5-hydroxytryptamine release by tramadol, fenfluramine and reserpine". European Journal of Pharmacology 349 (2–3): 199–203. May 1998. doi:10.1016/S0014-2999(98)00195-2. PMID 9671098. 
  18. "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 of Neurochemistry 82 (6): 1435–43. September 2002. doi:10.1046/j.1471-4159.2002.01073.x. PMID 12354291. 
  19. "Replacing Opioids: Developing drugs to treat pain". https://www.analyticalcannabis.com/articles/replacing-opioids-developing-drugs-to-treat-pain-289925. 
  20. Oxford Textbook of Palliative Medicine, 3rd ed. (Doyle D, Hanks G, Cherney I and Calman K, eds. Oxford University Press, 2004).
  21. "Opioid-induced hyperalgesia: where are we now?". Current Opinion in Supportive and Palliative Care 9 (2): 116–21. June 2015. doi:10.1097/SPC.0000000000000137. PMID 25872113. 
  22. 22.0 22.1 22.2 "Interrelations between pain and alcohol: An integrative review". Clinical Psychology Review 37: 57–71. April 2015. doi:10.1016/j.cpr.2015.02.005. PMID 25766100. 
  23. "Alcohol related changes in regulation of NMDA receptor functions". Current Neuropharmacology 6 (1): 39–54. March 2008. doi:10.2174/157015908783769662. PMID 19305787. 
  24. "Medicinal cannabis". Australian Prescriber 38 (6): 212–5. December 2015. doi:10.18773/austprescr.2015.072. PMID 26843715. 
  25. "What is medical marijuana?". July 2015. https://www.drugabuse.gov/publications/drugfacts/marijuana-medicine. "The term medical marijuana refers to using the whole unprocessed marijuana plant or its basic extracts to treat a disease or symptom." 
  26. "The pharmacologic and clinical effects of medical cannabis". Pharmacotherapy 33 (2): 195–209. February 2013. doi:10.1002/phar.1187. PMID 23386598. 
  27. "Cannabinoids for Medical Use: A Systematic Review and Meta-analysis". JAMA 313 (24): 2456–73. 23 June 2015. doi:10.1001/jama.2015.6358. PMID 26103030. http://jama.jamanetwork.com/data/journals/jama/934167/joi150059.pdf. 
  28. "Medical Marijuana and Chronic Pain: a Review of Basic Science and Clinical Evidence". Current Pain and Headache Reports 19 (10): 50. October 2015. doi:10.1007/s11916-015-0524-x. PMID 26325482. 
  29. "Neuropharmacological basis for multimodal analgesia in chronic pain". Postgraduate Medicine 134 (3): 245–259. October 2021. doi:10.1080/00325481.2021.1985351. PMID 34636261. 
  30. "The efficacy of combination analgesic therapy in relieving dental pain". Journal of the American Dental Association 133 (7): 861–71. July 2002. doi:10.14219/jada.archive.2002.0300. PMID 12148679. 
  31. "Combination analgesics in adults". Australian Prescriber (33): 113–5. http://www.australianprescriber.com/magazine/33/4/113/5. Retrieved 12 August 2010. 
  32. 32.0 32.1 *"Herbal medicine for low-back pain". The Cochrane Database of Systematic Reviews 2014 (12): CD004504. December 2014. doi:10.1002/14651858.CD004504.pub4. PMID 25536022. 
  33. "Nefopam analgesia and its role in multimodal analgesia: A review of preclinical and clinical studies". Clinical and Experimental Pharmacology & Physiology 43 (1): 3–12. January 2016. doi:10.1111/1440-1681.12506. PMID 26475417. 
  34. "Flupirtine shows functional NMDA receptor antagonism by enhancing Mg2+ block via activation of voltage independent potassium channels. Rapid communication". Journal of Neural Transmission 106 (9–10): 857–67. 1999. doi:10.1007/s007020050206. PMID 10599868. 
  35. "Flupirtine: pharmacology and clinical applications of a nonopioid analgesic and potentially neuroprotective compound". Expert Opinion on Pharmacotherapy 10 (9): 1495–500. June 2009. doi:10.1517/14656560902988528. PMID 19505216. 
  36. "Positive reinforcing effects of flupirtine--two case reports". Progress in Neuro-Psychopharmacology & Biological Psychiatry 34 (6): 1120–1. August 2010. doi:10.1016/j.pnpbp.2010.03.031. PMID 20362025. 
  37. "Do the potential benefits outweigh the risks? An update on the use of ziconotide in clinical practice". European Journal of Pain 22 (7): 1193–1202. August 2018. doi:10.1002/ejp.1229. PMID 29635804. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-149838. 
  38. "The use of NMDA-receptor antagonists in the treatment of chronic pain". The Clinical Journal of Pain 16 (2 Suppl): S73-9. June 2000. doi:10.1097/00002508-200006001-00013. PMID 10870744. 
  39. "Dextromethorphan shows efficacy in experimental pain (nociception) and opioid tolerance". Neurology (NEUROLOGY, 2005) 45 (12 Suppl 8): S66-8. December 1995. doi:10.1212/WNL.45.12_Suppl_8.S66. PMID 8545027. 
  40. "NDMA on Lower Back Pain". The Gold Rush CCXXIX (Cincinnati): 38. 1 May 2015. http://buytramadolpainrelief.blogspot.ca/. Retrieved 12 December 2015. 
  41. "Drugs Used In The Treatment Of Interstitial Cystitis". Drug Treatment in Urology. John Wiley & Sons, 2008. p. 65. 
  42. Voltaren Gel (diclofenac sodium topical gel) 1% – Hepatic Effects Labeling Changes
  43. [1]
  44. "Topical NSAIDs for acute musculoskeletal pain in adults". The Cochrane Database of Systematic Reviews 6 (6): CD007402. June 2015. doi:10.1002/14651858.CD007402.pub3. PMID 26068955. 
  45. 45.0 45.1 45.2 45.3 45.4 Brayfield, A, ed. "Martindale: The Complete Drug Reference". Medicines Complete. Pharmaceutical Press. http://www.medicinescomplete.com/mc/martindale/current/. 
  46. 46.0 46.1 46.2 46.3 Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. 2010. ISBN 978-0-07-162442-8. 
  47. 47.0 47.1 47.2 47.3 47.4 47.5 47.6 47.7 47.8 Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. 2013. ISBN 978-0-9805790-9-3. 
  48. 48.0 48.1 48.2 Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-084-8. https://archive.org/details/bnf65britishnati0000unse. 
  49. "Zorprin, Bayer Buffered Aspirin (aspirin) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. http://reference.medscape.com/drug/zorprin-bayer-buffered-aspirin-343279#showall. 
  50. "Seractil 300mg Film-Coated Tablets – Summary of Product Characteristics". electronic Medicines Compendium. Genus Pharmaceuticals. 30 September 2005. http://www.medicines.org.uk/emc/medicine/16949/SPC/Seractil+300mg+Film-Coated+Tablets/. 
  51. "Single dose oral dexibuprofen [S(+)-ibuprofen for acute postoperative pain in adults"]. The Cochrane Database of Systematic Reviews 10 (10): CD007550. October 2013. doi:10.1002/14651858.CD007550.pub3. PMID 24151035. 
  52. 52.0 52.1 "Cardiovascular safety of Cox-2 inhibitors and non-selective NSAIDs". MHRA. 26 July 2013. http://www.mhra.gov.uk/Safetyinformation/Generalsafetyinformationandadvice/Product-specificinformationandadvice/Product-specificinformationandadvice-A-F/CardiovascularsafetyofCOX-2inhibitorsandnon-selectiveNSAIDs/. 
  53. "(diflunisal) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. http://reference.medscape.com/drug/diflunisal-343285#showall. 
  54. "Nalfon (fenoprofen) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. http://reference.medscape.com/drug/nalfon-fenoprofen-343287#showall. 
  55. 55.0 55.1 (PDF) Flurbiprofen. Profiles of Drug Substances, Excipients and Related Methodology. 37. 2012. pp. 113–81. doi:10.1016/B978-0-12-397220-0.00004-0. ISBN 9780123972200. https://www.researchgate.net/publication/223981944. 
  56. "Pharmacokinetics of intravenous ibuprofen: implications of time of infusion in the treatment of pain and fever". Drugs 72 (3): 327–37. February 2012. doi:10.2165/11599230-000000000-00000. PMID 22316349. 
  57. "Oral ibuprofen versus intravenous ibuprofen or intravenous indomethacin for the treatment of patent ductus arteriosus in preterm infants: a systematic review and meta-analysis". Neonatology 102 (1): 9–15. 2012. doi:10.1159/000335332. PMID 22414850. 
  58. "Evidence-based use of indomethacin and ibuprofen in the neonatal intensive care unit". Clinics in Perinatology 39 (1): 111–36. March 2012. doi:10.1016/j.clp.2011.12.002. PMID 22341541. 
  59. "Arthrexin Indomethacin PRODUCT INFORMATION" (PDF). TGA eBusiness Services. Alphapharm Pty Limited. 14 October 2011. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-04968-3. 
  60. "Ketoprofen 2.5% gel: a clinical overview". European Review for Medical and Pharmacological Sciences 15 (8): 943–9. August 2011. PMID 21845805. 
  61. "Physical characteristics, pharmacological properties and clinical efficacy of the ketoprofen patch: a new patch formulation". European Review for Medical and Pharmacological Sciences 15 (7): 823–30. July 2011. PMID 21780552. 
  62. "Ketoprofen pharmacokinetics, efficacy, and tolerability in pediatric patients". Paediatric Drugs 12 (5): 313–29. October 2010. doi:10.2165/11534910-000000000-00000. PMID 20799760. 
  63. "Biowaiver monographs for immediate-release solid oral dosage forms: ketoprofen". Journal of Pharmaceutical Sciences 101 (10): 3593–603. October 2012. doi:10.1002/jps.23233. PMID 22786667. 
  64. "Pain and ketoprofen: what is its role in clinical practice?". Reumatismo 62 (3): 172–88. July–September 2010. doi:10.4081/reumatismo.2010.172. PMID 21052564. 
  65. "NAME OF THE MEDICINE TORADOL (ketorolac trometamol)" (PDF). TGA eBusiness Services. ROCHE PRODUCTS PTY LIMITED. 3 February 2012. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-01084-3. 
  66. "Ketorolac 0.45% ophthalmic solution". Drugs & Aging 28 (7): 583–9. July 2011. doi:10.2165/11207450-000000000-00000. PMID 21721602. 
  67. "Ketorolac tromethamine formulations: an overview". Expert Opinion on Drug Delivery 6 (9): 961–75. September 2009. doi:10.1517/17425240903116006. PMID 19663721. 
  68. "Perioperative single dose ketorolac to prevent postoperative pain: a meta-analysis of randomized trials". Anesthesia and Analgesia 114 (2): 424–33. February 2012. doi:10.1213/ANE.0b013e3182334d68. PMID 21965355. 
  69. "Intranasal ketorolac: for short-term pain management". Clinical Drug Investigation 32 (6): 361–71. June 2012. doi:10.2165/11209240-000000000-00000. PMID 22574632. 
  70. "A review of intranasal ketorolac tromethamine for the short-term management of moderate to moderately severe pain that requires analgesia at the opioid level". Current Medical Research and Opinion 28 (12): 1873–80. December 2012. doi:10.1185/03007995.2012.744302. PMID 23098098. 
  71. "Ketorolac in the treatment of acute migraine: a systematic review". Headache 53 (2): 277–87. February 2013. doi:10.1111/head.12009. PMID 23298250. 
  72. "Ketorolac therapy for the prevention of acute pseudophakic cystoid macular edema: a systematic review". Eye 26 (2): 252–8. February 2012. doi:10.1038/eye.2011.296. PMID 22094296. 
  73. "Lornoxicam. A review of its pharmacology and therapeutic potential in the management of painful and inflammatory conditions". Drugs 51 (4): 639–57. April 1996. doi:10.2165/00003495-199651040-00008. PMID 8706598. 
  74. "Clinical pharmacokinetics of lornoxicam. A short half-life oxicam". Clinical Pharmacokinetics 34 (6): 421–8. June 1998. doi:10.2165/00003088-199834060-00001. PMID 9646006. 
  75. "PRODUCT INFORMATION PONSTAN CAPSULES (mefenamic acid)" (PDF). TGA eBusiness Services. Pfizer Australia Pty Ltd. 12 October 2012. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-03251-3. 
  76. "Relafen (nabumetone) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. http://reference.medscape.com/drug/relafen-nabumetone-343295#showall. 
  77. "Naproxen. A reappraisal of its pharmacology, and therapeutic use in rheumatic diseases and pain states". Drugs 40 (1): 91–137. July 1990. doi:10.2165/00003495-199040010-00006. PMID 2202585. 
  78. "Daypro (oxaprozin) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. http://reference.medscape.com/drug/daypro-oxaprozin-343297#showall. 
  79. "Oxaprozin. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy". Drugs 32 (4): 291–312. October 1986. doi:10.2165/00003495-198632040-00001. PMID 3536423. 
  80. "CHEMMART PIROXICAM CAPSULES" (PDF). TGA eBusiness Services. Apotex Pty Ltd. 18 December 2013. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-06214-3. 
  81. "Piroxicam. A reappraisal of its pharmacology and therapeutic efficacy". Drugs 28 (4): 292–323. October 1984. doi:10.2165/00003495-199448060-00007. PMID 6386426. 
  82. "(salsalate) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. http://reference.medscape.com/drug/salsalate-343340#showall. 
  83. "Aclin Sulindac" (PDF). TGA eBusiness Services. Alphapharm Pty Limited. 8 November 2011. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-04956-3. 
  84. "Tenoxicam. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy". Drugs 34 (3): 289–310. September 1987. doi:10.2165/00003495-198734030-00001. PMID 3315620. 
  85. "Clinical pharmacokinetics of tiaprofenic acid and its enantiomers". Clinical Pharmacokinetics 31 (5): 331–47. November 1996. doi:10.2165/00003088-199631050-00002. PMID 9118583. 
  86. "Tolmetin: a review of its pharmacological properties and therapeutic efficacy in rheumatic diseases". Drugs 15 (6): 429–50. June 1978. doi:10.2165/00003495-197815060-00002. PMID 350558. 
  87. "Celecoxib: a review of its use for symptomatic relief in the treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis". Drugs 71 (18): 2457–89. December 2011. doi:10.2165/11208240-000000000-00000. PMID 22141388. 
  88. "Etodolac. A preliminary review of its pharmacodynamic activity and therapeutic use". Drugs 31 (4): 288–300. April 1986. doi:10.2165/00003495-198631040-00002. PMID 2940079. 
  89. "Etodolac. A reappraisal of its pharmacology and therapeutic use in rheumatic diseases and pain states". Drugs 42 (2): 274–99. August 1991. doi:10.2165/00003495-199142020-00008. PMID 1717225. 
  90. "Etodolac clinical pharmacokinetics". Clinical Pharmacokinetics 26 (4): 259–74. April 1994. doi:10.2165/00003088-199426040-00003. PMID 8013160. 
  91. "Clinical pharmacokinetic and pharmacodynamic profile of etoricoxib". Clinical Pharmacokinetics 47 (11): 703–20. 2008. doi:10.2165/00003088-200847110-00002. PMID 18840026. 
  92. "Lumiracoxib in the management of osteoarthritis and acute pain". Expert Opinion on Pharmacotherapy 8 (10): 1551–64. July 2007. doi:10.1517/14656566.8.10.1551. PMID 17661736. https://zenodo.org/record/897825. 
  93. "Clinical pharmacokinetics of meloxicam. A cyclo-oxygenase-2 preferential nonsteroidal anti-inflammatory drug". Clinical Pharmacokinetics 36 (2): 115–26. February 1999. doi:10.2165/00003088-199936020-00003. PMID 10092958. 
  94. "PRODUCT INFORMATION DYNASTAT parecoxib (as sodium)" (PDF). TGA eBusiness Services. Pfizer Australia Pty Ltd. 6 February 2013. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-01151-3. 
  95. "Rofecoxib". Drugs 58 (3): 499–505; discussion 506–7. September 1999. doi:10.2165/00003495-199958030-00016. PMID 10493277. 
  96. "Rofecoxib". Expert Opinion on Pharmacotherapy 1 (5): 1053–66. July 2000. doi:10.1517/14656566.1.5.1053. PMID 11249495. 
  97. "Valdecoxib". Drugs 62 (14): 2059–71; discussion 2072–3. 2002. doi:10.2165/00003495-200262140-00005. PMID 12269850. 
  98. "Buprenex, Subutex (buprenorphine) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. http://reference.medscape.com/drug/subutex-buprenorphine-343326#showall. 
  99. "PRODUCT INFORMATION ACTACODE" (PDF). TGA eBusiness Services. Aspen Pharma Pty Ltd. 19 September 2006. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-01565-3. 
  100. "Zohydro ER (hydrocodone) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. http://reference.medscape.com/drug/zohydro-er-hydrocodone-343312#showall. 
  101. "Dilaudid, Dilaudid HP (hydromorphone) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. http://reference.medscape.com/drug/dilaudid-hydromorphone-343313#showall. 
  102. "Roxicodone, OxyContin (oxycodone) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. http://reference.medscape.com/drug/roxicodone-oxycontin-oxycodone-343321#showall. 
  103. "Opana, Opana ER (oxymorphone) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. http://reference.medscape.com/drug/opana-er-oxymorphone-343322#showall. 
  104. "Stadol (butorphanol) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. http://reference.medscape.com/drug/butorphanol-343327#showall. 
  105. 105.0 105.1 "Levorphanol: the forgotten opioid". Supportive Care in Cancer 15 (3): 259–64. March 2007. doi:10.1007/s00520-006-0146-2. PMID 17039381. 
  106. "Levo Dromoran (levorphanol) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. http://reference.medscape.com/drug/levorphanol-343314#showall. 
  107. "Nubain (nalbuphine) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. http://reference.medscape.com/drug/nalbuphine-343329#showall. 
  108. "Nalbuphine. A preliminary review of its pharmacological properties and therapeutic efficacy". Drugs 26 (3): 191–211. September 1983. doi:10.2165/00003495-198326030-00002. PMID 6137354. 
  109. "Pentazocine: a review of its pharmacological properties, therapeutic efficacy and dependence liability". Drugs 5 (1): 6–91. 1973. doi:10.2165/00003495-197305010-00002. PMID 4578369. 
  110. "Talwin (pentazocine) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. http://reference.medscape.com/drug/talwin-pentazocine-343330#showall. 
  111. "Single-dose kinetics and bioavailability of ketobemidone". Acta Anaesthesiologica Scandinavica. Supplementum 74: 59–62. 1982. doi:10.1111/j.1399-6576.1982.tb01848.x. PMID 6124079. 
  112. "Demerol, Pethidine (meperidine) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. http://reference.medscape.com/drug/demerol-meperidine-343315#showall. 
  113. "Should New Zealand continue signing up to the Pethidine Protocol?". The New Zealand Medical Journal 119 (1230): U1875. March 2006. PMID 16532042. http://journal.nzma.org.nz/journal/119-1230/1875/content.pdf. 
  114. "Meperidine: a critical review". American Journal of Therapeutics 9 (1): 53–68. January–February 2002. doi:10.1097/00045391-200201000-00010. PMID 11782820. 
  115. "Strategy to Eliminate Pethidine Use in Hospitals". Journal of Pharmacy Practice and Research 38 (2): 88–89. 2008. doi:10.1002/j.2055-2335.2008.tb00807.x. 
  116. "Clinical pharmacokinetics of pethidine". Clinical Pharmacokinetics 3 (5): 352–68. September–October 1978. doi:10.2165/00003088-197803050-00002. PMID 359212. 
  117. "Dipipanone 10mg + Cyclizine 30mg Tablets – Summary of Product Characteristics". 22 August 2012. http://www.medicines.org.uk/emc/medicine/26936/SPC/Dipipanone+10+mg+%2b+Cyclizine+30+mg+Tablets/. 
  118. "Meptazinol. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy". Drugs 30 (4): 285–312. October 1985. doi:10.2165/00003495-198530040-00001. PMID 2998723. 
  119. "Pharmacokinetics of methadone". Journal of Pain & Palliative Care Pharmacotherapy 19 (4): 13–24. 2005. doi:10.1080/J354v19n04_05. PMID 16431829. 
  120. "Marinol (dronabinol) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. http://reference.medscape.com/drug/marinol-thc-dronabinol-342047#showall. 
  121. "Cymbalta (duloxetine) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. http://reference.medscape.com/drug/cymbalta-duloxetine-342960#showall. 
  122. "Flupirtine, a re-discovered drug, revisited". Inflammation Research 62 (3): 251–8. March 2013. doi:10.1007/s00011-013-0592-5. PMID 23322112. 
  123. "Flupirtine in pain management: pharmacological properties and clinical use". CNS Drugs 24 (10): 867–81. October 2010. doi:10.2165/11536230-000000000-00000. PMID 20839897. 
  124. "Savella (milnacipran) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. http://reference.medscape.com/drug/savella-milnacipran-345054#showall. 
  125. "Nefopam for the prevention of postoperative pain: quantitative systematic review". British Journal of Anaesthesia 101 (5): 610–7. November 2008. doi:10.1093/bja/aen267. PMID 18796441. 
  126. "Tylenol, Tylenol Infants' Drops (acetaminophen) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. http://reference.medscape.com/drug/tylenol-acetaminophen-343346#showall. 
  127. "Pregabalin: in the treatment of postherpetic neuralgia". Drugs & Aging 26 (10): 883–92. 2009. doi:10.2165/11203750-000000000-00000. PMID 19761281. 
  128. 128.0 128.1 "Prialt (ziconotide) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. http://reference.medscape.com/drug/prialt-ziconotide-343378#showall. 
  129. "Breaking barriers to novel analgesic drug development". Nature Reviews. Drug Discovery 16 (8): 545–564. August 2017. doi:10.1038/nrd.2017.87. PMID 28596533. 

Sources