Analgesic

Tilidine, a brand of painkiller

An analgesic or painkiller is any member of the group of drugs used to achieve analgesia, relief from pain.

Analgesic drugs act in various ways on the peripheral and central nervous systems. They are distinct from anesthetics, which reversibly eliminate sensation. Analgesics include paracetamol (known in North America as acetaminophen or simply APAP), the non-steroidal anti-inflammatory drugs (NSAIDs) such as the salicylates, and opioid drugs such as morphine and oxycodone.

In choosing analgesics, the severity and response to other medication determines the choice of agent; the World Health Organization (WHO) pain ladder^[1] specifies mild analgesics as its first step.

Analgesic choice is also determined by the type of pain: For neuropathic pain, traditional analgesics are less effective, and there is often benefit from classes of drugs that are not normally considered analgesics, such as tricyclic antidepressants and anticonvulsants.^[2]

Name

The word analgesic derives from Greek an- (ἀν-, "without"), álgos (ἄλγος, "pain"),^[3] and -ikos (-ικος, forming adjectives). Such drugs were usually known as anodynes before the 20th century.^[4][5]

Major classes

Paracetamol and NSAIDs

The exact mechanism of action of paracetamol/acetaminophen is uncertain but appears to act centrally in the brain rather than peripherally in nerve endings. Aspirin and the other non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenases, leading to a decrease in prostaglandin production. In contrast to paracetamol and the opioids, this reduces not only pain but inflammation as well.

Paracetamol has few side-effects and is regarded as generally safe in low and infrequent doses as prescribed, or per manufacturer's instructions, otherwise use can lead to potentially life-threatening liver damage and occasionally kidney damage. Side effects include bloody or black, tarry stools, bloody or cloudy urine, fever with or without chills (not present before treatment and not caused by the condition being treated), pain in the lower back and/or side (severe and/or sharp), pinpoint red spots on the skin, skin rash, hives, or itching, sore throat (not present before treatment and not caused by the condition being treated), sores, ulcers, or white spots on the lips or in the mouth, sudden decrease in the amount of urine, unusual bleeding or bruising, unusual tiredness or weakness, yellow eyes or skin.^[6]

While paracetamol is usually taken orally or rectally, an intravenous preparation introduced in 2002 has been shown to improve pain relief and reduce opioid consumption in the perioperative setting.

NSAIDs can predispose to in some patients peptic ulcers, renal failure, allergic reactions, and occasionally tinnitus with excess dosage, and they can increase the risk of hemorrhage by affecting platelet function. The use of aspirin in children under 16 suffering from viral illness has been linked to Reye's syndrome, a rare but severe liver disorder.

COX-2 inhibitors

These drugs have been derived from NSAIDs. The cyclooxygenase enzyme inhibited by NSAIDs was discovered to have at least 2 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.^[7]

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.^[7]

Opioids

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.^[8] 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.^{[9][10][11][12]} 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 a 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.

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.^[13]

When used appropriately, opioids and other central analgesics are otherwise 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 so, when safe to do so, the dosage may need to be increased to maintain effectiveness. This may be of particular concern regarding patients suffering with chronic pain. 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.

Flupirtine

Flupirtine is a centrally acting K+ channel opener with weak NMDA antagonist properties.^[14] It is used in Europe for moderate to strong pain and migraine and its muscle-relaxant properties. It has no 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.^[15] However, tolerance may develop in single cases.^[16]

Specific agents

In patients with chronic or neuropathic pain, various other substances may have analgesic properties. Tricyclic antidepressants, especially clomipramine and amitriptyline, have been shown to improve pain in what appears to be a central manner. Nefopam is used in Europe for pain relief with concurrent opioids. The exact mechanism of carbamazepine, gabapentin, and pregabalin is similarly unclear, but these anticonvulsants are used to treat neuropathic pain with differing degrees of success. Anticonvulsants are most commonly used for neuropathic pain as their mechanism of action tends to inhibit pain sensation.^[17]

Specific forms and uses

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 allergy sufferers.

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 combatting pain at multiple sites of action,^[18] 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.^[19]

Topical or systemic

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.^[20]); capsaicin also is used topically. Lidocaine, an anesthetic, and steroids may be injected into painful 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 blood stream 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.^[21]

Psychotropic agents

Tetrahydrocannabinol (THC) and some other cannabinoids, either from the Cannabis sativa plant or synthetic, have analgesic properties, although the use of cannabis derivatives is currently illegal in many countries. A recent study finds that inhaled cannabis is effective in alleviating neuropathy and pain resulting from, e.g., spinal injury and multiple sclerosis.^[22] Other psychotropic analgesic agents include ketamine (an NMDA receptor antagonist), clonidine and other α₂-adrenoreceptor agonists, and mexiletine and other local anaesthetic analogues.

Atypical, adjuvant analgesics & potentiators

Drugs that have been introduced for uses other than analgesics are also used in pain management. Both first-generation (such as amitriptyline) and newer anti-depressants (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 nefopam, orphenadrine, pregabalin, gabapentin, cyclobenzaprine, 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 tolerance to opioids and exert additional analgesia by acting upon the NMDA receptors; some analgesics such as methadone and ketobemidone and perhaps piritramide have intrinsic NMDA action.

High-alcohol liquor, two forms of which 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.

The use of adjuvant analgesics is an important and growing part of the pain-control field and new discoveries are made practically every year. Many of these drugs combat the side-effects of opioid analgesics, an added bonus. For example, antihistamines including orphenadrine combat the release of histamine caused by many opioids. Stimulants such as methylphenidate, caffeine, ephedrine, dextroamphetamine, methamphetamine, and cocaine work against heavy sedation and may elevate mood in distressed patients as do the antidepressants. The use of medicinal cannabis remains a debated issue.

Comparison of available agents

Comparison of different analgesics

Generic name (INN)	Physicochemistry[23]	Mechanism of action[24]	Routes of administration [24][25][26]	Pharmacokinetics[23]	Indications [24][25][26]	Major safety concerns [24][25][26]
Non-steroidal anti-inflammatory agents
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 ibuprofen.	PO.	Protein binding > 99%; half-life = 4 hours; metabolised to diclofenac (minor); excretion = urine (67%).	As per ibuprofen.	As per ibuprofen.
Acemetacin	Comes in free form; practically insoluble in water, soluble in certain organic solvents; degrades upon contact with light. Chemically related to indometacin	As above.	PO.	Slightly metabolised to indometacin.	Rheumatoid arthritis, osteoarthritis and lower back pain.	As above.
Amfenac	No available data.	As above.	PO.	No data.	Pain and inflammation.	As above.
Aminophenazone	Related to phenylbutazone.	As above.	PO.	Not available.	Musculoskeletal and joint disorders.	Agranulocytosis and cancer.
Ampiroxicam	Related to piroxicam.	As above.	PO.	No data.	Rheumatoid arthritis and osteoarthritis.	Photosensitivity and other AEs typical of NSAIDs.
Amtolmetin guacil	Prodrug to tolmetin.	As above.	PO.	No data.	As above.	As above.
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%.[27]	Blood thining; 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 ibuprofen.	PO, rectal.	No data available.	Rheumatoid arthritis; gout; ankylosing spondylitis.	As per ibuprofen.
Bendazac	Comes in free acid and lysine salt forms. Chemically related to indometacin.	As per acetametacin.	Topical, ophthalmologic.	N/A	Skin conditions and cataracts.	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 above.	Topical, PO, rectal, spray and vaginal.	No data available.	Musculoskeletal disorders; soft-tissue disorders; sore throat.	As above.
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.	As per other topical NSAIDs.
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 ibuprofen.
Clonixin	Comes in free acid and lysine salt forms.	Reversible COX-1/COX-2 inhibition.	PO, IM, IV, rectal.	No data.	Pain.	As above.
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%).[28]	Osteoarthritis; mild-moderate pain and menstrual pain.[29]	As above.
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 infarctions, strokes and hypertension. More prone to causing these AEs compared to the other non-selective NSAIDs.[30]
Diethylamine salicylate	Freely soluble in water; degrades upon contact with light and iron.	As above.	Topical.	N/A.	Rheumatic and musculoskeletal pain.	As per other topical NSAIDs.
Diflunisal	Comes in free acid and arginine salt forms; practically insoluble in water, soluble in ethanol; degrades upon contact with light.	As above.	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%).[23][31]	Pain; osteoarthritis; rheumatoid arthritis.	As above.
Epirizole	Comes in free form.	As above.	PO.	Not available.	Rheumatoid arthritis.	As above.
Ethenzamide	Comes in free form; salicylate.	As above.	PO.	Not available.	Musculoskeletal pain; fever.	As above.
Etofenamate	Liquid; practically insoluble in water, miscible with ethyl acetate and methanol.	As above.	Topical.	Not available.	Musculoskeletal, joint and soft-tissue disorders.	As per topical NSAIDs.
Felbinac	Comes in free and diisopropanolamine salt forms; practically insoluble in water and ethanol, soluble in methanol.	As above.	Topical.	N/A	Musculoskeletal pain and soft tissue injuries.	As per topical NSAIDs.
Fenbufen	Comes as free acid; fairly insoluble in most solvents (including water); propionic acid derivative.	As above.	PO.	Protein binding > 99%; half-life = 10–17 hours.	As above.	As above.
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 above.	PO.	Bioavailability = ?; protein binding = 99%; hepatic metabolism; excretion = urine, faeces.[32]	Pain; rheumatoid arthritis and osteoarthritis.	As above.
Fentiazac	Comes in free form and calcium salt; acetic acid derivative.	As above.	PO.	No data.	As above.	As above.
Fepradinol	Comes in free acid and hydrochloride salt forms.	As above.	Topical.	N/A	Local inflammatory response.	As per other topical NSAIDs.
Feprazone	Comes in free acid and piperazine salt forms. Phenylbutazone.	As above.	Rectal, topical.	Not available.	As above.	As above.
Floctafenine	Comes in free acid form; anthranilic acid derivative.	As above.	Oral.	Extensively metabolised by the liver; half-life = 8 hours; excretion = urinary and biliary.	Short-term relief from pain.	As above.
Flufenamic acid	Comes in free acid form and aluminium salt form; anthranilic acid.	As above.	Topical.	N/A	Soft tissue inflammation and pain.	Topical effects.
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 above.	PO, IM, IV, ophthalmologic.	Bioavailability = 96% (oral); protein binding > 99%; volume of distribution = 0.12 L/kg; excretion = urine (70%).[33]	Ophthalmologic: Vernal keratoconjunctivitis; postoperative ocular swelling; herpetic stromal keratitis, excimer laser photorefractive keratectomy; ocular gingivitis. Systemic use: rheumatoid arthritis; osteoarthritis.[33]	As above.
Glucametacin	Indometacin derivative.	As above.	PO.	Not available.	Musculoskeletal, joint, peri-articular and soft-tissue disorders.	As per other systemic NSAIDs.
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 above.	PO, IV, topical	Bioavailability = 80–100%; protein binding = 90–99%; hepatic metabolism, mostly via CYP2C9 and CYP2C19-mediated oxidation; excretion = Urine (50–60%), faeces.[34]	Pain; fever; inflammatory illness; rheumatoid arthritis; osteoarthritis; heavy menstrual bleeding; patent ductus arteriosus.[25][35][36]	As above.
Imidazole salicylate	Comes in free form. Salicylate.	As above.	PO, rectal, topical.	Not available.	Muscular and rheumatic pain.	As above.
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 above.	PO, IV, rectal	Bioavailability = 100% (oral); protein binding = 90%; hepatic metabolism; excretion = urine (60%), faeces (33%).[37]	Rheumatoid arthritis; osteoarthritis; gout; ankylosing spondylitis; period pain; patent ductus arteriosus.[25]	As above.
Isonixin	Comes in free form.	As above.	PO, rectal and topical.	Not available.	Musculoskeletal and joint disorders.	As above.
Kebuzone	Comes in free and sodium salt form; phenylbutazone derivative.	As above.	IM, PO.	Not available.	As above.	As above.
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 above.	PO, rectal, topical, transdermal, intravenous, intramuscular.[38][39]	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).[40][41]	Rheumatoid arthritis, osteoarthritis and superficial sporting injuries (topical use).[25][42]	As above.
Ketorolac	Comes in the trometamol salt form; highly soluble in water. Degrades in the presence of light. Acetic acid derivative.	As above.	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%).[43]	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.[44][45][46][47][48][49][50]	As above.
Lornoxicam	Hydrochloride salt form used; oxicam derivative.	As above.	PO.	Protein binding = 99%; volume of distribution = 0.2 L/kg; half-life = 3–5 hours; excretion = faeces (51%), urine (42%).[51][52]	Acute and chronic pain.	As above.
Loxoprofen	Comes in sodium salt form. Propionic acid derivative.	As above.	Topical.	N/A	Local inflammation and pain.	As above.
Magnesium salicylate	Comes in free form; soluble in water and ethanol; salicylate.	As above.	PO.	Not available.	As above.	As above.
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 above.	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%).[23]	Osteoarthritis; rheumatoid arthritis; mild-moderate pain; dysmenorrhoea; menorrhagia.	As per other systemic NSAIDs.
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 above.	PO.	Protein binding extensive; hepatic metabolism, mostly via CYP2C9; half-life = 2 hours; excretion = urine (66%), faeces (20–25%).[53]	Inflammatory pain and heavy menstrual bleeding.[25]	As above.
Mofezolac	Comes in free form.	As above.	PO.	Not available.	Musculoskeletal and joint pain.	As above.
Morniflumate	Comes in free acid form; niflumic acid derivative.	As above.	PO, rectal.	Not available.	Inflammatory conditions.	As above.
Nabumetone	Comes in free acid form; practically insoluble in water, freely soluble in acetone; degrades on contact with air and light.	As above.	PO.	Protein binding = 99%; hepatically metabolised; half-life = 24 hours; excretion = urine (80%), faeces (9%).[54]	Osteoarthritis; rheumatoid arthritis.	As above.
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 above.	PO.	Bioavailability = ?; protein binding > 99.5%; volume of distribution = 10% of bodyweight; half-life = 12–15 hours; excretion = urine (95%), faeces (<3%).[55]	Rheumatoid arthritis; osteoarthritis; ankylosing spondylitis; juvenile idiopathic arthritis; inflammatory pain; heavy menstrual bleeding.	As above; less prone to causing thrombotic events compared to other non-selective NSAIDs.[30]
Nepafenac	Comes in free form; related to amfenac.	As above.	Ophthalmologic.	Unavailable.	Inflammation and pain following cataract surgery.	As per other ophthalmologic NSAIDs.
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 above.	PO, rectal (ethyl ester, morniflumate).	Unavailable.	Musculoskeletal, joint and mouth inflammatory disorders.	As above.
Oxaprozin	Comes in potassium and free acid forms; degrades upon contact with light. Propionic acid derivative.	As above.	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%).[56][57]	Osteoarthritis; rheumatoid arthritis.	As above.
Oxyphenbutazone	Comes in free form. Phenylbutazone.	As above.	PO, Ophthalmologic.	Unavailable.	Ophthalmologic: Episcleritis. Systemic (now seldom used due to adverse effects): ankylosing spondylitis; rheumatoid arthritis; osteoarthritis.	As per other ophthalmologic NSAIDs. For systemic use haematological side effects such as aplastic anaemia; agranulocytosis; leucopenia; neutropenia; etc.
Phenazone	No data.	As above.	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 above.	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 above.	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 above.	PO, topical.	Protein binding = 99%; extensively hepatically metabolised; half-life = 36–45 hours; excretion = urine, faeces.[58][59]	Rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and sports injuries (topical use).[25]	As above.
Proglumetacin	Comes in maleate salt form; indometacin derivative.	As above.	PO, rectal, topical.	Not available.	Musculoskeletal and joint disorders.	As above.
Proquazone	Comes in free form.	As above.	PO, rectal.	Not available.	As above.	As above.
Pranoprofen	No data.	As above.	PO, ophthalmologic.	Not available.	Pain, inflammation and fever.	As above.
Salamidacetic acid	Comes in sodium and diethylamine salt forms; salicylate.	As above.	PO.	Unavailable.	Musculoskeletal disorders.	As above.
Salicylamide	Fairly insoluble in water and chloroform; soluble in most other organic solvents; salicylate.	As above.	PO, topical.	No data.	Muscular and rheumatic diseases.	As above.
Salol	No data.	As above.	PO, topical.	No data.	Lower urinary tract infections.	As above.
Salsalate	Degrades upon contact with air; salicylate derivative.	As above.	PO.	Hepatic metabolism; half-life = 7–8 hours; excretion = urine.[60]	Rheumatoid arthritis, osteoarthritis.	As above.
Sodium salicylate	Freely soluble in water; degrades upon contact with air and light; salicylate.	As above.	PO, IV, topical.	No data.	Pain, fever and rheumatic conditions.	Cardiac problems; otherwise as above.
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 above.	PO, rectal.	Bioavailability = 90%; protein binding = 93% (sulindac), 98% (active metabolite); hepatic metabolism; excretion = urine (50%), faeces (25%).[61]	Rheumatoid arthritis; osteoarthritis; gout; ankylosing spondylitis; inflammatory pain.[25]	As above.
Suxibuzone	Practically insoluble in water, soluble in ethanol and acetone; phenylbutazone.	As above.	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 above.	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%).[62]	Osteoarthritis; rheumatoid arthritis; soft tissue injury.	As above.
Tetridamine	No data.	As above.	Vaginal.	No data.	Vaginitis.	As above.
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 above.	PO.	Protein binding > 99%; volume of distribution = 0.1–0.2 L/kg; hepatic metabolism; half-life = 2–4 hours.[63]	Ankylosing spondylitis; osteoarthritis; rheumatoid arthritis; fibrosis; capsulitis; soft-tissue disorders.	As above.
Tiaramide	No data.	As above.	PO.	No data.	Pain; inflammation.	As above.
Tinoridine	No data.	As above.	No data.	No data.	Pain; inflammation.	As above.
Tolfenamic acid	Comes as free acid; practically insoluble in water; degrades upon contact with light; anthranilic acid.	As above.	PO.	Protein binding = 99%; half-life = 2 hours; hepatically metabolised; excretion = urine (90%), faeces.	Migraine; osteoarthritis; rheumatoid arthritis; dysmenorrhoea.	As above.
Tolmetin	Comes in sodium salt form; freely soluble in water, slightly soluble in ethanol, freely soluble in methanol. Acetic acid derivative.	As above.	PO.	Protein binding > 99%; volume of distribution = 7–10 L; half-life = 1 hour; excretion = urine (90%).[64]	Osteoarthritis; rheumatoid arthritis.	As above.
Ufenamate	No data.	No data.	Topical.	No data.	Inflammatory skin disorders.	As per other topical NSAIDs.
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%).[65]	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 above.	PO.	Bioavailability = ?; protein binding > 99%; volume of distribution = 0.41 L/kg; half-life = 6–7 hours; excretion = urine (73%).[66][67][68]	Rheumatoid arthritis, including juvenile idiopathic arthritis; osteoarthritis; acute pain.	As above.
Etoricoxib	Comes in free form; sulfonamide.	As above.	PO.	Bioavailability = 100%; protein binding = 91.4%; volume of distribution = 120 L; half-life = 22 hours; hepatic metabolism; excretion = urine (70%), faeces (20%).[69]	Acute pain; gout; osteoarthritis.	As above.
Lumiracoxib†	Comes in free form; acetic acid derivative.	As above.	PO.	Bioavailability = 74%; protein binding > 98%; extensive hepatic metabolism, mostly via CYP2C9; half-life = 3–6 hours; excretion = Urine (50%), faeces (50%).[70]	Osteoarthritis.	As above, plus hepatotoxicity.
Meloxicam	Comes in free form; fairly insoluble in water and in most organic solvents; oxicam derivative.	As above.	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%).[71]	Osteoarthritis; rheumatoid arthritis.	As above.
Nimesulide	Comes in free and betadex form; practically insoluble in water and ethanol, soluble in acetone.	As above.	PO, rectal, topical.	Unavailable.	Acute pain; dysmenorrhoea; sprains (topical); tendinitis.	As above.
Parecoxib	Comes in sodium salt form; sulfonamide.	As above.	IM, IV.	Plasma binding = 98%; volume of distribution = 55 L; hepatic metabolism, mostly via CYP2C9, CYP3A4; half-life = 8 hours; excretion = urine (70%).[72]	Postoperative pain.	As above.
Rofecoxib†	Comes in free form; sulfonamide.	As above.	PO.	Bioavailability = 93%; protein binding = 87%; hepatic metabolism; half-life = 17 hours.[73][74]	Acute pain; osteoarthritis; rheumatoid arthritis.	As above.
Valdecoxib†	Comes in free form; sulfonamide.	As above.	PO.	Bioavailability = 83%; protein binding = 98%; hepatic metabolism, mostly via CYP3A4 and CYP2C9; half-life = 8.11 hours; excretion = urine (90%).[75]	Pain from dysmenorrhoea; rheumatoid arthritis; osteoarthritis.	As above and also potentially fatal skin reactions (e.g. toxic epidermal necrolysis).
Opioids
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.[76]	Opioid dependence, moderate-severe pain.	As per other opioids, 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%).[77]	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 above. 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 above.
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 above.
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.[78]	Chronic pain.	As above.
Hydromorphone	Comes in hydrochloride salt form; freely soluble in water, fairly insoluble in organic solvents; degrades upon contact with light or temperatures outside 15 °C and 35 °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.[79]	Moderate-severe pain; cough.	As above.
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 above.
Nicomorphine	Dinicotinic acid ester derivative of morphine.	As above.	IM, IV, PO, rectal, SC.	No available data.	Moderate-severe pain.	As above.
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%).[80]	Moderate-severe pain.	As above.
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 °C to 30 °C.	As above.	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.[81]	Postoperative analgesia/anaesthesia; moderate-severe pain.	As above.
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 °C and 30 °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.[82]	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 °C and 30 °C; phenanthrene derivative.	Mu opioid; NMDA antagonist; SNRI.[83]	PO, IM, IV, SC.	Protein binding = 40%; extensive first-pass metabolism; half-life = 12–16 hours, 30 hours (repeated dosing).[83][84]	Acute/chronic pain.	As above.
Nalbuphine	Comes primarily as its hydrochloride salt.	Full agonist at kappa opioid receptors, partial agonist/antagonist at the mu opioid receptors.[23]	IM, IV, SC.	Protein binding = not significant; hepatic metabolism; half-life = 5 hours; excretion = urine, faeces.[85][86]	Pain; anaesthesia supplement; opioid-induced pruritus.	As above. Respiratory depression is subject to ceiling effect.
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 above.
Eptazocine	Comes as hydrobromide salt.	As above.	IM, SC.	No data.	Moderate-severe pain.	As above.
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.[87][88]	Moderate-severe pain.	As above. Respiratory effects are subject to a ceiling effect.
Phenylpiperidines
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 other opioids.
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.[89]	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).[90][91][92][93][94]	Moderate-severe pain.	As per other opioids; and seizures, anxiety, mood changes and serotonin syndrome.
Open-chain opioids
Dextromoramide	Comes in tartrate salt and free forms; soluble in water (tartrate salt).	IM, IV, PO, rectal.	No data available.	Severe pain.	As per other opioids.	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.[95]	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 °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.[96]	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 °C and 30 °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.[97]	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 °C and 30 °C and upon contact with light.	Mu opioid (mostly via its active metabolite, O-desmethyltramadol) and 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.
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 °C and 30 °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 °C and 30 °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.
Other analgesics
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%).[98]	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%).[99]	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.[100]	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.[101]
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%).[102]	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 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.[103]
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.[104]	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%).[105]	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%).[106]	Chronic pain.	CNS toxicity (abnormal gait, abnormal vision, memory problems, etc.); GI effects.[106]
Where † indicates products that are no longer marketed.

Novel analgesics

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.

See also

• Audioanalgesia
• Pain management
• Patient-controlled analgesia
• Pain in babies
• Congenital analgesia (insensitivity to pain)

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