Analgesic

Summary

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
Drug class
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 
Legal status
In Wikidata

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 edit

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 edit

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

 
A bottle of acetaminophen

Paracetamol (acetaminophen) edit

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 edit

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 edit

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 edit

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 edit

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 edit

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 edit

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 edit

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 edit

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 edit

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. 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.[citation needed]

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.[40]

Other uses edit

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.[41]); 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.[42]

Uses edit

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.[43]

List of drugs with comparison edit


Research edit

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.[128]

See also edit

References edit

Citations edit

  1. ^ Dworkin RH, Backonja M, Rowbotham MC, Allen RR, Argoff CR, Bennett GJ, et al. (November 2003). "Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations". Archives of Neurology. 60 (11): 1524–34. doi:10.1001/archneur.60.11.1524. PMID 14623723.
  2. ^ Harper D (2001). "Online Etymology Dictionary: Analgesia". Archived from the original on March 3, 2014. Retrieved December 3, 2012.
  3. ^ EB (1878).
  4. ^ EB (1911).
  5. ^ "British National Formulary: Analgesics". BNF online. Retrieved 8 June 2017.
  6. ^ a b c "Acetaminophen". The American Society of Health-System Pharmacists. Archived from the original on 2016-06-05.
  7. ^ Scottish Intercollegiate Guidelines Network (SIGN) (2008). "6.1 and 7.1.1" (PDF). Guideline 106: Control of pain in adults with cancer. Scotland: National Health Service (NHS). ISBN 9781905813384. Archived (PDF) from the original on 2010-12-20.
  8. ^ a b c Hochhauser D (2014). Cancer and its Management. John Wiley & Sons. p. 119. ISBN 9781118468715. Archived from the original on 2017-09-10.
  9. ^ Russell FM, Shann F, Curtis N, Mulholland K (2003). "Evidence on the use of paracetamol in febrile children". Bulletin of the World Health Organization. 81 (5): 367–72. PMC 2572451. PMID 12856055.
  10. ^ Mallinson T (2017). "A review of ketorolac as a prehospital analgesic". Journal of Paramedic Practice. 9 (12): 522–526. doi:10.12968/jpar.2017.9.12.522. Retrieved 2 June 2018.
  11. ^ Mallinson T (2017). "A review of ketorolac as a prehospital analgesic". Journal of Paramedic Practice. London: MA Healthcare. 9 (12): 522–526. doi:10.12968/jpar.2017.9.12.522. Archived from the original on 5 June 2018. Retrieved 2 June 2018.
  12. ^ Warden SJ (April 2010). "Prophylactic use of NSAIDs by athletes: a risk/benefit assessment". The Physician and Sportsmedicine. 38 (1): 132–8. doi:10.3810/psm.2010.04.1770. PMID 20424410. S2CID 44567896. Archived from the original on 2010-11-26.
  13. ^ a b Conaghan PG (June 2012). "A turbulent decade for NSAIDs: update on current concepts of classification, epidemiology, comparative efficacy, and toxicity". Rheumatology International. 32 (6): 1491–502. doi:10.1007/s00296-011-2263-6. PMC 3364420. PMID 22193214.
  14. ^ Smith HS, Raffa RB, Pergolizzi JV, Taylor R, Tallarida RJ (July 2014). "Combining opioid and adrenergic mechanisms for chronic pain". Postgraduate Medicine. 126 (4): 98–114. doi:10.3810/pgm.2014.07.2788. PMID 25141248. S2CID 19782818.
  15. ^ Driessen B, Reimann W (January 1992). "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. doi:10.1111/j.1476-5381.1992.tb14226.x. PMC 1908625. PMID 1596676.
  16. ^ Bamigbade TA, Davidson C, Langford RM, Stamford JA (September 1997). "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. doi:10.1093/bja/79.3.352. PMID 9389855.
  17. ^ Reimann W, Schneider F (May 1998). "Induction of 5-hydroxytryptamine release by tramadol, fenfluramine and reserpine". European Journal of Pharmacology. 349 (2–3): 199–203. doi:10.1016/S0014-2999(98)00195-2. PMID 9671098.
  18. ^ Gobbi M, Moia M, Pirona L, Ceglia I, Reyes-Parada M, Scorza C, Mennini T (September 2002). "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. doi:10.1046/j.1471-4159.2002.01073.x. hdl:10533/173421. PMID 12354291. S2CID 13397864.
  19. ^ Tozer A. "Replacing Opioids: Developing drugs to treat pain". Analytical Cannabis. Archived from the original on 22 August 2017. Retrieved 22 August 2017.
  20. ^ Oxford Textbook of Palliative Medicine, 3rd ed. (Doyle D, Hanks G, Cherney I and Calman K, eds. Oxford University Press, 2004).
  21. ^ Bannister K (June 2015). "Opioid-induced hyperalgesia: where are we now?". Current Opinion in Supportive and Palliative Care. 9 (2): 116–21. doi:10.1097/SPC.0000000000000137. PMID 25872113. S2CID 13922218.
  22. ^ a b c Zale EL, Maisto SA, Ditre JW (April 2015). "Interrelations between pain and alcohol: An integrative review". Clinical Psychology Review. 37: 57–71. doi:10.1016/j.cpr.2015.02.005. PMC 4385458. PMID 25766100.
  23. ^ Nagy J (March 2008). "Alcohol related changes in regulation of NMDA receptor functions". Current Neuropharmacology. 6 (1): 39–54. doi:10.2174/157015908783769662. PMC 2645546. PMID 19305787.
  24. ^ Murnion B (December 2015). "Medicinal cannabis". Australian Prescriber. 38 (6): 212–5. doi:10.18773/austprescr.2015.072. PMC 4674028. PMID 26843715.
  25. ^ "What is medical marijuana?". National Institute of Drug Abuse. July 2015. Archived from the original on 17 April 2016. Retrieved 19 April 2016. The term medical marijuana refers to using the whole unprocessed marijuana plant or its basic extracts to treat a disease or symptom.
  26. ^ Borgelt LM, Franson KL, Nussbaum AM, Wang GS (February 2013). "The pharmacologic and clinical effects of medical cannabis". Pharmacotherapy. 33 (2): 195–209. doi:10.1002/phar.1187. PMID 23386598. S2CID 8503107.
  27. ^ Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, et al. (23 June 2015). "Cannabinoids for Medical Use: A Systematic Review and Meta-analysis" (PDF). JAMA. 313 (24): 2456–73. doi:10.1001/jama.2015.6358. hdl:10757/558499. PMID 26103030. Archived (PDF) from the original on 21 September 2017.
  28. ^ Jensen B, Chen J, Furnish T, Wallace M (October 2015). "Medical Marijuana and Chronic Pain: a Review of Basic Science and Clinical Evidence". Current Pain and Headache Reports. 19 (10): 50. doi:10.1007/s11916-015-0524-x. PMID 26325482. S2CID 9110606.
  29. ^ Patel R, Dickenson AH (October 2021). "Neuropharmacological basis for multimodal analgesia in chronic pain". Postgraduate Medicine. 134 (3): 245–259. doi:10.1080/00325481.2021.1985351. PMID 34636261. S2CID 238635838.
  30. ^ Mehlisch DR (July 2002). "The efficacy of combination analgesic therapy in relieving dental pain". Journal of the American Dental Association. 133 (7): 861–71. doi:10.14219/jada.archive.2002.0300. PMID 12148679.
  31. ^ Murnion B. "Combination analgesics in adults". Australian Prescriber (33): 113–5. Archived from the original on 25 March 2012. Retrieved 12 August 2010.
  32. ^ a b *Oltean H, Robbins C, van Tulder MW, Berman BM, Bombardier C, Gagnier JJ (December 2014). "Herbal medicine for low-back pain". The Cochrane Database of Systematic Reviews. 2014 (12): CD004504. doi:10.1002/14651858.CD004504.pub4. PMC 7197042. PMID 25536022. S2CID 4498929.
    • Cameron M, Gagnier JJ, Chrubasik S (February 2011). "Herbal therapy for treating rheumatoid arthritis". The Cochrane Database of Systematic Reviews (2): CD002948. doi:10.1002/14651858.CD002948.pub2. PMID 21328257.
    • Cui X, Trinh K, Wang YJ (January 2010). "Chinese herbal medicine for chronic neck pain due to cervical degenerative disc disease". The Cochrane Database of Systematic Reviews. 2010 (1): CD006556. doi:10.1002/14651858.CD006556.pub2. PMC 7389878. PMID 20091597.
  33. ^ Girard P, Chauvin M, Verleye M (January 2016). "Nefopam analgesia and its role in multimodal analgesia: A review of preclinical and clinical studies". Clinical and Experimental Pharmacology & Physiology. 43 (1): 3–12. doi:10.1111/1440-1681.12506. PMID 26475417.
  34. ^ Kornhuber J, Bleich S, Wiltfang J, Maler M, Parsons CG (1999). "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. doi:10.1007/s007020050206. PMID 10599868. S2CID 11636934.
  35. ^ Klawe C, Maschke M (June 2009). "Flupirtine: pharmacology and clinical applications of a nonopioid analgesic and potentially neuroprotective compound". Expert Opinion on Pharmacotherapy. 10 (9): 1495–500. doi:10.1517/14656560902988528. PMID 19505216. S2CID 11597721.
  36. ^ Stoessel C, Heberlein A, Hillemacher T, Bleich S, Kornhuber J (August 2010). "Positive reinforcing effects of flupirtine--two case reports". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 34 (6): 1120–1. doi:10.1016/j.pnpbp.2010.03.031. PMID 20362025. S2CID 19710997.
  37. ^ Bäckryd E (August 2018). "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. doi:10.1002/ejp.1229. PMID 29635804. S2CID 4710528.
  38. ^ Hewitt DJ (June 2000). "The use of NMDA-receptor antagonists in the treatment of chronic pain". The Clinical Journal of Pain. 16 (2 Suppl): S73-9. doi:10.1097/00002508-200006001-00013. PMID 10870744. S2CID 40067641.
  39. ^ Elliott KJ, Brodsky M, Hyanansky A, Foley KM, Inturrisi CE (December 1995). "Dextromethorphan shows efficacy in experimental pain (nociception) and opioid tolerance". Neurology. NEUROLOGY, 2005. 45 (12 Suppl 8): S66-8. doi:10.1212/WNL.45.12_Suppl_8.S66. PMID 8545027. S2CID 46279174.
  40. ^ Eardley I, Whelan P, Kirby R, Schaeffer A. "Drugs Used In The Treatment Of Interstitial Cystitis". Drug Treatment in Urology. John Wiley & Sons, 2008. p. 65.
  41. ^ Voltaren Gel (diclofenac sodium topical gel) 1% – Hepatic Effects Labeling Changes Archived 2014-01-08 at the Wayback Machine
  42. ^ [1] Archived October 19, 2010, at the Wayback Machine
  43. ^ Derry S, Moore RA, Gaskell H, McIntyre M, Wiffen PJ (June 2015). "Topical NSAIDs for acute musculoskeletal pain in adults". The Cochrane Database of Systematic Reviews. 6 (6): CD007402. doi:10.1002/14651858.CD007402.pub3. PMC 6426435. PMID 26068955.
  44. ^ a b c d e Brayfield, A (ed.). "Martindale: The Complete Drug Reference". Medicines Complete. Pharmaceutical Press. Retrieved 9 April 2014.
  45. ^ a b c d Brunton L, Chabner B, Knollman B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07-162442-8.
  46. ^ a b c d e f g h i Rossi S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
  47. ^ a b c Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-084-8.
  48. ^ "Zorprin, Bayer Buffered Aspirin (aspirin) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 7 April 2014. Retrieved 6 April 2014.
  49. ^ "Seractil 300mg Film-Coated Tablets – Summary of Product Characteristics". electronic Medicines Compendium. Genus Pharmaceuticals. 30 September 2005. Archived from the original on 13 April 2014. Retrieved 7 April 2014.
  50. ^ Derry S, Best J, Moore RA (October 2013). "Single dose oral dexibuprofen [S(+)-ibuprofen] for acute postoperative pain in adults". The Cochrane Database of Systematic Reviews. 10 (10): CD007550. doi:10.1002/14651858.CD007550.pub3. PMC 4170892. PMID 24151035.
  51. ^ a b "Cardiovascular safety of Cox-2 inhibitors and non-selective NSAIDs". MHRA. 26 July 2013. Archived from the original on April 13, 2014. Retrieved 7 April 2014.
  52. ^ "(diflunisal) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 13 April 2014. Retrieved 7 April 2014.
  53. ^ "Nalfon (fenoprofen) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 13 April 2014. Retrieved 7 April 2014.
  54. ^ a b Abdel-Aziz AA, Al-Badr AA, Hafez GA (2012). Flurbiprofen (PDF). Profiles of Drug Substances, Excipients and Related Methodology. Vol. 37. pp. 113–81. doi:10.1016/B978-0-12-397220-0.00004-0. ISBN 9780123972200. PMID 22469318.
  55. ^ Smith HS, Voss B (February 2012). "Pharmacokinetics of intravenous ibuprofen: implications of time of infusion in the treatment of pain and fever". Drugs. 72 (3): 327–37. doi:10.2165/11599230-000000000-00000. PMID 22316349. S2CID 207301513.
  56. ^ Neumann R, Schulzke SM, Bührer C (2012). "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. doi:10.1159/000335332. PMID 22414850. S2CID 40750585.
  57. ^ Johnston PG, Gillam-Krakauer M, Fuller MP, Reese J (March 2012). "Evidence-based use of indomethacin and ibuprofen in the neonatal intensive care unit". Clinics in Perinatology. 39 (1): 111–36. doi:10.1016/j.clp.2011.12.002. PMC 3598606. PMID 22341541.
  58. ^ "Arthrexin Indomethacin PRODUCT INFORMATION" (PDF). TGA eBusiness Services. Alphapharm Pty Limited. 14 October 2011. Archived from the original on 15 October 2015. Retrieved 7 April 2014.
  59. ^ Coaccioli S (August 2011). "Ketoprofen 2.5% gel: a clinical overview". European Review for Medical and Pharmacological Sciences. 15 (8): 943–9. PMID 21845805.
  60. ^ Adachi H, Ioppolo F, Paoloni M, Santilli V (July 2011). "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. PMID 21780552.
  61. ^ Kokki H (October 2010). "Ketoprofen pharmacokinetics, efficacy, and tolerability in pediatric patients". Paediatric Drugs. 12 (5): 313–29. doi:10.2165/11534910-000000000-00000. PMID 20799760. S2CID 207298956.
  62. ^ Shohin IE, Kulinich JI, Ramenskaya GV, Abrahamsson B, Kopp S, Langguth P, et al. (October 2012). "Biowaiver monographs for immediate-release solid oral dosage forms: ketoprofen". Journal of Pharmaceutical Sciences. 101 (10): 3593–603. doi:10.1002/jps.23233. PMID 22786667. S2CID 31263593.
  63. ^ Sarzi-Puttini P, Atzeni F, Lanata L, Bagnasco M, Colombo M, Fischer F, D'Imporzano M (July–September 2010). "Pain and ketoprofen: what is its role in clinical practice?". Reumatismo. 62 (3): 172–88. doi:10.4081/reumatismo.2010.172. hdl:2434/667356. PMID 21052564.
  64. ^ "NAME OF THE MEDICINE TORADOL (ketorolac trometamol)" (PDF). TGA eBusiness Services. ROCHE PRODUCTS PTY LIMITED. 3 February 2012. Archived from the original on 15 October 2015. Retrieved 7 April 2014.
  65. ^ McCormack PL (July 2011). "Ketorolac 0.45% ophthalmic solution". Drugs & Aging. 28 (7): 583–9. doi:10.2165/11207450-000000000-00000. PMID 21721602. S2CID 36573017.
  66. ^ Sinha VR, Kumar RV, Singh G (September 2009). "Ketorolac tromethamine formulations: an overview". Expert Opinion on Drug Delivery. 6 (9): 961–75. doi:10.1517/17425240903116006. PMID 19663721. S2CID 25006837.
  67. ^ De Oliveira GS, Agarwal D, Benzon HT (February 2012). "Perioperative single dose ketorolac to prevent postoperative pain: a meta-analysis of randomized trials". Anesthesia and Analgesia. 114 (2): 424–33. doi:10.1213/ANE.0b013e3182334d68. PMID 21965355. S2CID 21022357.
  68. ^ Garnock-Jones KP (June 2012). "Intranasal ketorolac: for short-term pain management". Clinical Drug Investigation. 32 (6): 361–71. doi:10.2165/11209240-000000000-00000. PMID 22574632. S2CID 41818971.
  69. ^ He A, Hersh EV (December 2012). "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. doi:10.1185/03007995.2012.744302. PMID 23098098. S2CID 25001604.
  70. ^ Taggart E, Doran S, Kokotillo A, Campbell S, Villa-Roel C, Rowe BH (February 2013). "Ketorolac in the treatment of acute migraine: a systematic review". Headache. 53 (2): 277–87. doi:10.1111/head.12009. PMID 23298250. S2CID 12843704.
  71. ^ Yilmaz T, Cordero-Coma M, Gallagher MJ (February 2012). "Ketorolac therapy for the prevention of acute pseudophakic cystoid macular edema: a systematic review". Eye. 26 (2): 252–8. doi:10.1038/eye.2011.296. PMC 3272202. PMID 22094296.
  72. ^ Balfour JA, Fitton A, Barradell LB (April 1996). "Lornoxicam. A review of its pharmacology and therapeutic potential in the management of painful and inflammatory conditions". Drugs. 51 (4): 639–57. doi:10.2165/00003495-199651040-00008. PMID 8706598. S2CID 265522598.
  73. ^ Skjodt NM, Davies NM (June 1998). "Clinical pharmacokinetics of lornoxicam. A short half-life oxicam". Clinical Pharmacokinetics. 34 (6): 421–8. doi:10.2165/00003088-199834060-00001. PMID 9646006. S2CID 46662001.
  74. ^ "PRODUCT INFORMATION PONSTAN CAPSULES (mefenamic acid)" (PDF). TGA eBusiness Services. Pfizer Australia Pty Ltd. 12 October 2012. Archived from the original on 15 October 2015. Retrieved 7 April 2014.
  75. ^ "Relafen (nabumetone) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 13 April 2014. Retrieved 7 April 2014.
  76. ^ Todd PA, Clissold SP (July 1990). "Naproxen. A reappraisal of its pharmacology, and therapeutic use in rheumatic diseases and pain states". Drugs. 40 (1): 91–137. doi:10.2165/00003495-199040010-00006. PMID 2202585. S2CID 195692083.
  77. ^ "Daypro (oxaprozin) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 13 April 2014. Retrieved 7 April 2014.
  78. ^ Todd PA, Brogden RN (October 1986). "Oxaprozin. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy". Drugs. 32 (4): 291–312. doi:10.2165/00003495-198632040-00001. PMID 3536423. S2CID 195692751.
  79. ^ "CHEMMART PIROXICAM CAPSULES" (PDF). TGA eBusiness Services. Apotex Pty Ltd. 18 December 2013. Archived from the original on 15 October 2015. Retrieved 7 April 2014.
  80. ^ Brogden RN, Heel RC, Speight TM, Avery GS (October 1984). "Piroxicam. A reappraisal of its pharmacology and therapeutic efficacy". Drugs. 28 (4): 292–323. doi:10.2165/00003495-199448060-00007. PMID 6386426. S2CID 209070732.
  81. ^ "(salsalate) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 13 April 2014. Retrieved 7 April 2014.
  82. ^ "Aclin Sulindac" (PDF). TGA eBusiness Services. Alphapharm Pty Limited. 8 November 2011. Archived from the original on 15 October 2015. Retrieved 7 April 2014.
  83. ^ Gonzalez JP, Todd PA (September 1987). "Tenoxicam. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy". Drugs. 34 (3): 289–310. doi:10.2165/00003495-198734030-00001. PMID 3315620. S2CID 195698431.
  84. ^ Davies NM (November 1996). "Clinical pharmacokinetics of tiaprofenic acid and its enantiomers". Clinical Pharmacokinetics. 31 (5): 331–47. doi:10.2165/00003088-199631050-00002. PMID 9118583. S2CID 25446820.
  85. ^ Brogden RN, Heel RC, Speight TM, Avery GS (June 1978). "Tolmetin: a review of its pharmacological properties and therapeutic efficacy in rheumatic diseases". Drugs. 15 (6): 429–50. doi:10.2165/00003495-197815060-00002. PMID 350558. S2CID 33403236.
  86. ^ McCormack PL (December 2011). "Celecoxib: a review of its use for symptomatic relief in the treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis". Drugs. 71 (18): 2457–89. doi:10.2165/11208240-000000000-00000. PMID 22141388. S2CID 71357689.
  87. ^ Lynch S, Brogden RN (April 1986). "Etodolac. A preliminary review of its pharmacodynamic activity and therapeutic use". Drugs. 31 (4): 288–300. doi:10.2165/00003495-198631040-00002. PMID 2940079. S2CID 195692567.
  88. ^ Balfour JA, Buckley MM (August 1991). "Etodolac. A reappraisal of its pharmacology and therapeutic use in rheumatic diseases and pain states". Drugs. 42 (2): 274–99. doi:10.2165/00003495-199142020-00008. PMID 1717225. S2CID 195693229.
  89. ^ Brocks DR, Jamali F (April 1994). "Etodolac clinical pharmacokinetics". Clinical Pharmacokinetics. 26 (4): 259–74. doi:10.2165/00003088-199426040-00003. PMID 8013160. S2CID 43007023.
  90. ^ Takemoto JK, Reynolds JK, Remsberg CM, Vega-Villa KR, Davies NM (2008). "Clinical pharmacokinetic and pharmacodynamic profile of etoricoxib". Clinical Pharmacokinetics. 47 (11): 703–20. doi:10.2165/00003088-200847110-00002. PMID 18840026. S2CID 11718396.
  91. ^ Bannwarth B, Bérenbaum F (July 2007). "Lumiracoxib in the management of osteoarthritis and acute pain". Expert Opinion on Pharmacotherapy. 8 (10): 1551–64. doi:10.1517/14656566.8.10.1551. PMID 17661736. S2CID 22656859.
  92. ^ Davies NM, Skjodt NM (February 1999). "Clinical pharmacokinetics of meloxicam. A cyclo-oxygenase-2 preferential nonsteroidal anti-inflammatory drug". Clinical Pharmacokinetics. 36 (2): 115–26. doi:10.2165/00003088-199936020-00003. PMID 10092958. S2CID 9873285.
  93. ^ "PRODUCT INFORMATION DYNASTAT parecoxib (as sodium)" (PDF). TGA eBusiness Services. Pfizer Australia Pty Ltd. 6 February 2013. Archived from the original on 15 October 2015. Retrieved 7 April 2014.
  94. ^ Scott LJ, Lamb HM (September 1999). "Rofecoxib". Drugs. 58 (3): 499–505, discussion 506–7. doi:10.2165/00003495-199958030-00016. PMID 10493277. S2CID 219216087.
  95. ^ Hillson JL, Furst DE (July 2000). "Rofecoxib". Expert Opinion on Pharmacotherapy. 1 (5): 1053–66. doi:10.1517/14656566.1.5.1053. PMID 11249495. S2CID 219291177.
  96. ^ Ormrod D, Wellington K, Wagstaff AJ (2002). "Valdecoxib". Drugs. 62 (14): 2059–71, discussion 2072–3. doi:10.2165/00003495-200262140-00005. PMID 12269850. S2CID 250308600.
  97. ^ "Buprenex, Subutex (buprenorphine) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 13 April 2014. Retrieved 9 April 2014.
  98. ^ "PRODUCT INFORMATION ACTACODE" (PDF). TGA eBusiness Services. Aspen Pharma Pty Ltd. 19 September 2006. Archived from the original on 15 October 2015. Retrieved 8 April 2014.
  99. ^ "Zohydro ER (hydrocodone) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 13 April 2014. Retrieved 8 April 2014.
  100. ^ "Dilaudid, Dilaudid HP (hydromorphone) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 13 April 2014. Retrieved 8 April 2014.
  101. ^ "Roxicodone, OxyContin (oxycodone) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 13 April 2014. Retrieved 8 April 2014.
  102. ^ "Opana, Opana ER (oxymorphone) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 13 April 2014. Retrieved 8 April 2014.
  103. ^ "Stadol (butorphanol) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 13 April 2014. Retrieved 8 April 2014.
  104. ^ a b Prommer E (March 2007). "Levorphanol: the forgotten opioid". Supportive Care in Cancer. 15 (3): 259–64. doi:10.1007/s00520-006-0146-2. PMID 17039381. S2CID 10916508.
  105. ^ "Levo Dromoran (levorphanol) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 13 April 2014. Retrieved 9 April 2014.
  106. ^ "Nubain (nalbuphine) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 13 April 2014. Retrieved 9 April 2014.
  107. ^ Errick JK, Heel RC (September 1983). "Nalbuphine. A preliminary review of its pharmacological properties and therapeutic efficacy". Drugs. 26 (3): 191–211. doi:10.2165/00003495-198326030-00002. PMID 6137354. S2CID 196363445.
  108. ^ Brogden RN, Speight TM, Avery GS (1973). "Pentazocine: a review of its pharmacological properties, therapeutic efficacy and dependence liability". Drugs. 5 (1): 6–91. doi:10.2165/00003495-197305010-00002. PMID 4578369. S2CID 28014084.
  109. ^ "Talwin (pentazocine) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 13 April 2014. Retrieved 9 April 2014.
  110. ^ Anderson P, Arnér S, Bondesson U, Boréus LO, Hartvig P (1982). "Single-dose kinetics and bioavailability of ketobemidone". Acta Anaesthesiologica Scandinavica. Supplementum. 74: 59–62. doi:10.1111/j.1399-6576.1982.tb01848.x. PMID 6124079. S2CID 35733660.
  111. ^ "Demerol, Pethidine (meperidine) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 8 April 2014. Retrieved 9 April 2014.
  112. ^ Shipton E (March 2006). "Should New Zealand continue signing up to the Pethidine Protocol?" (PDF). The New Zealand Medical Journal. 119 (1230): U1875. PMID 16532042. Archived from the original (PDF) on April 8, 2014.
  113. ^ Latta KS, Ginsberg B, Barkin RL (January–February 2002). "Meperidine: a critical review". American Journal of Therapeutics. 9 (1): 53–68. doi:10.1097/00045391-200201000-00010. PMID 11782820. S2CID 23410891.
  114. ^ MacPherson RD, Duguid MD (2008). "Strategy to Eliminate Pethidine Use in Hospitals". Journal of Pharmacy Practice and Research. 38 (2): 88–89. doi:10.1002/j.2055-2335.2008.tb00807.x. S2CID 71812645.
  115. ^ Mather LE, Meffin PJ (September–October 1978). "Clinical pharmacokinetics of pethidine". Clinical Pharmacokinetics. 3 (5): 352–68. doi:10.2165/00003088-197803050-00002. PMID 359212. S2CID 35402662.
  116. ^ "Dipipanone 10mg + Cyclizine 30mg Tablets – Summary of Product Characteristics". 22 August 2012. Archived from the original on 13 April 2014. Retrieved 9 April 2014.
  117. ^ Holmes B, Ward A (October 1985). "Meptazinol. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy". Drugs. 30 (4): 285–312. doi:10.2165/00003495-198530040-00001. PMID 2998723. S2CID 208818234.
  118. ^ Lugo RA, Satterfield KL, Kern SE (2005). "Pharmacokinetics of methadone". Journal of Pain & Palliative Care Pharmacotherapy. 19 (4): 13–24. doi:10.1080/J354v19n04_05. PMID 16431829. S2CID 29509469.
  119. ^ "Marinol (dronabinol) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 13 April 2014. Retrieved 9 April 2014.
  120. ^ "Cymbalta (duloxetine) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 13 April 2014. Retrieved 9 April 2014.
  121. ^ Szelenyi I (March 2013). "Flupirtine, a re-discovered drug, revisited". Inflammation Research. 62 (3): 251–8. doi:10.1007/s00011-013-0592-5. PMID 23322112. S2CID 16535456.
  122. ^ Devulder J (October 2010). "Flupirtine in pain management: pharmacological properties and clinical use". CNS Drugs. 24 (10): 867–81. doi:10.2165/11536230-000000000-00000. PMID 20839897. S2CID 22053483.
  123. ^ "Savella (milnacipran) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 13 April 2014. Retrieved 9 April 2014.
  124. ^ Evans MS, Lysakowski C, Tramèr MR (November 2008). "Nefopam for the prevention of postoperative pain: quantitative systematic review". British Journal of Anaesthesia. 101 (5): 610–7. doi:10.1093/bja/aen267. PMID 18796441.
  125. ^ "Tylenol, Tylenol Infants' Drops (acetaminophen) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 14 April 2014. Retrieved 8 April 2014.
  126. ^ McKeage K, Keam SJ (2009). "Pregabalin: in the treatment of postherpetic neuralgia". Drugs & Aging. 26 (10): 883–92. doi:10.2165/11203750-000000000-00000. PMID 19761281. S2CID 39007929.
  127. ^ a b "Prialt (ziconotide) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 13 April 2014. Retrieved 8 April 2014.
  128. ^ Yekkirala AS, Roberson DP, Bean BP, Woolf CJ (August 2017). "Breaking barriers to novel analgesic drug development". Nature Reviews. Drug Discovery. 16 (8): 545–564. doi:10.1038/nrd.2017.87. PMC 5675565. PMID 28596533.

Sources edit