Analgésico

Uma droga analgésica, também chamada simplesmente de analgésico (inglês americano), analgésico (inglês britânico), analgésico, ou analgésico, é qualquer membro do grupo de medicamentos usados para obter alívio da dor (isto é, analgesia ou controle da dor). Analgésicos são conceitualmente distintos dos anestésicos, que reduzem temporariamente e, em alguns casos, eliminam a sensação, embora a analgesia e a anestesia se sobreponham neurofisiologicamente e, portanto, várias drogas têm efeitos analgésicos e anestésicos.

A escolha do analgésico também é determinada pelo tipo de dor: para a dor neuropática, os analgésicos tradicionais são menos eficazes e muitas vezes há benefícios de classes de medicamentos que normalmente não são considerados analgésicos, como antidepressivos tricíclicos e anticonvulsivantes.

Vários analgésicos, como muitos AINEs, estão disponíveis sem receita na maioria dos países, enquanto vários outros são medicamentos prescritos devido aos riscos substanciais e altas chances de overdose, uso indevido e dependência na ausência de supervisão médica.

Etimologia

A palavra analgésico deriva do grego an- ( ἀν-, "sem"), álgos (ἄλγος, "pain") e -ikos (-ικος, formando adjetivos). Essas drogas eram geralmente conhecidas como anódinas antes do século XX.

Classificação

Os analgésicos são normalmente classificados com base em seu mecanismo de ação.

Paracetamol (acetaminofeno)

O paracetamol, também conhecido como acetaminofeno ou APAP, é um medicamento usado para tratar dor e febre. É normalmente usado para dor leve a moderada. Em combinação com analgésicos opioides, o paracetamol agora é usado para dores mais intensas, como dores oncológicas e após cirurgias. É normalmente usado por via oral ou retal, mas também está disponível por via intravenosa. Os efeitos duram entre duas e quatro horas. O paracetamol é classificado como um analgésico leve. O paracetamol é geralmente seguro nas doses recomendadas.

AINEs

Os antiinflamatórios não esteróides (geralmente abreviados para AINEs) são uma classe de medicamentos que agrupa medicamentos que diminuem a dor e a febre e, em doses mais altas, diminuem a inflamação. Os membros mais proeminentes desse grupo de medicamentos, aspirina, ibuprofeno e naproxeno, estão disponíveis sem receita na maioria dos países.

Inibidores de COX-2

Estas drogas foram derivadas de AINEs. Descobriu-se que a enzima ciclooxigenase inibida pelos AINEs tem pelo menos duas versões diferentes: COX1 e COX2. A pesquisa sugeriu que a maioria dos efeitos adversos dos AINEs é mediada pelo bloqueio da enzima COX1 (constitutiva), com os efeitos analgésicos sendo mediados pela enzima COX2 (induzível). Assim, os inibidores de COX2 foram desenvolvidos para inibir apenas a enzima COX2 (os AINEs tradicionais bloqueiam ambas as versões em geral). Esses medicamentos (como rofecoxib, celecoxib e etoricoxib) são analgésicos igualmente eficazes quando comparados aos AINEs, mas causam menos hemorragia gastrointestinal em particular.

Após a ampla adoção dos inibidores de COX-2, descobriu-se que a maioria dos medicamentos dessa classe aumenta o risco de eventos cardiovasculares em 40%, em média. Isso levou à retirada de rofecoxib e valdecoxib e advertências sobre outros. O etoricoxibe parece relativamente seguro, com risco de eventos trombóticos semelhante ao do AINE não coxibe diclofenaco.

Opioides

A morfina, o opioide arquetípico, e outros opioides (por exemplo, codeína, oxicodona, hidrocodona, dihidromorfina, petidina) exercem uma influência semelhante no sistema receptor de opioides cerebral. A buprenorfina é um agonista parcial do receptor μ-opióide, e o tramadol é um inibidor da recaptação de serotonina e norepinefrina (IRSN) com fracas propriedades agonistas do receptor μ-opióide. O tramadol é estruturalmente mais próximo da venlafaxina do que da codeína e fornece analgesia não apenas por fornecer analgesia "semelhante a opioides" (através do agonismo leve do receptor mu), mas também atuando como um agente liberador de serotonina fraco, mas de ação rápida, e inibidor da recaptação de norepinefrina. O tapentadol, com algumas semelhanças estruturais com o tramadol, apresenta o que se acredita ser uma nova droga que funciona através de dois (e possivelmente três) modos de ação diferentes, tanto na forma de um opioide tradicional quanto de um SNRI. Os efeitos da serotonina e norepinefrina sobre a dor, embora não completamente compreendidos, tiveram relações causais estabelecidas e drogas da classe dos IRSNs são comumente usadas em conjunto com opioides (especialmente tapentadol e tramadol) com maior sucesso no alívio da dor.

A dosagem de todos os opioides pode ser limitada pela toxicidade de opioides (confusão, depressão respiratória, espasmos mioclônicos e pupilas pontuais), convulsões (tramadol), mas indivíduos tolerantes a opioides geralmente têm tetos de dose mais altos do que pacientes sem tolerância. Os opioides, embora sejam analgésicos muito eficazes, podem ter alguns efeitos colaterais desagradáveis. Os pacientes que iniciam a morfina podem sentir náuseas e vômitos (geralmente aliviados por um curto período de antieméticos, como fenergan). Prurido (coceira) pode exigir a mudança para um opioide diferente. A constipação ocorre em quase todos os pacientes em uso de opioides, e laxantes (lactulose, contendo macrogol ou codantramero) são normalmente co-prescritos.

Quando usados adequadamente, os opioides e outros analgésicos centrais são seguros e eficazes; no entanto, podem ocorrer riscos como dependência e o corpo se acostumando com a droga (tolerância). O efeito de tolerância significa que o uso frequente da droga pode resultar em seu efeito diminuído. Quando for seguro, pode ser necessário aumentar a dosagem para manter a eficácia contra a tolerância, o que pode ser particularmente preocupante em pacientes com dor crônica e que requerem analgésicos por longos períodos. A tolerância a opioides é frequentemente tratada com terapia de rotação de opioides, na qual um paciente é rotineiramente alternado entre dois ou mais medicamentos opioides não tolerantes cruzados, a fim de evitar o excesso de dosagens seguras na tentativa de obter um efeito analgésico adequado.

A tolerância a opioides não deve ser confundida com hiperalgesia induzida por opioides. Os sintomas dessas duas condições podem parecer muito semelhantes, mas o mecanismo de ação é diferente. A hiperalgesia induzida por opioides ocorre quando a exposição a opioides aumenta a sensação de dor (hiperalgesia) e pode até tornar dolorosos estímulos não dolorosos (alodinia).

Álcool

O álcool tem efeitos biológicos, mentais e sociais que influenciam as consequências do uso de álcool para a dor. O uso moderado de álcool pode diminuir certos tipos de dor em determinadas circunstâncias.

A maioria de seus efeitos analgésicos vêm de receptores NMDA antagonizantes, de forma semelhante à cetamina, diminuindo assim a atividade do neurotransmissor excitatório primário (aumento de sinal), glutamato. Também funciona como um analgésico em menor grau, aumentando a atividade do neurotransmissor inibitório primário (redutor de sinal), GABA.

Também foi observado que a tentativa de usar álcool para tratar a dor leva a resultados negativos, incluindo consumo excessivo de álcool e transtorno por uso de álcool.

Maconha

Cannabis medicinal, ou maconha medicinal, refere-se à cannabis ou seus canabinóides usados para tratar doenças ou melhorar os sintomas. Há evidências sugerindo que a cannabis pode ser usada para tratar dores crônicas e espasmos musculares, com alguns estudos indicando melhor alívio da dor neuropática em relação aos opioides.

Combinações

Analgésicos são freqüentemente usados em combinação, como as preparações de paracetamol e codeína encontradas em muitos analgésicos sem receita. Eles também podem ser encontrados em combinação com drogas vasoconstritoras, como pseudoefedrina para preparações relacionadas ao sinus, ou com drogas anti-histamínicas para pessoas com alergias.

Embora o uso de paracetamol, aspirina, ibuprofeno, naproxeno e outros AINEs concomitantemente com opiáceos fracos a médios (até aproximadamente o nível de hidrocodona) tenha demonstrado efeitos sinérgicos benéficos ao combater a dor em vários locais de ação, vários produtos analgésicos combinados demonstraram ter poucos benefícios de eficácia quando comparados a doses semelhantes de seus componentes individuais. Além disso, essas combinações de analgésicos podem frequentemente resultar em eventos adversos significativos, incluindo overdoses acidentais, na maioria das vezes devido à confusão que surge dos componentes múltiplos (e muitas vezes inativos) dessas combinações.

Medicina alternativa

Existe alguma evidência de que alguns tratamentos usando medicina alternativa podem aliviar alguns tipos de dor de forma mais eficaz do que o placebo. A pesquisa disponível conclui que mais pesquisas seriam necessárias para entender melhor o uso da medicina alternativa.

Outras drogas

Nefopam—um inibidor da recaptação de monoamina e modulador dos canais de cálcio e sódio—também é aprovado para o tratamento de dor moderada a intensa em alguns países.

A flupirtina é um abridor de canal de K+ de ação central com fracas propriedades antagonistas de NMDA. Foi usado na Europa para dores moderadas a fortes, bem como para tratamento de enxaqueca e propriedades relaxantes musculares. Não possui propriedades anticolinérgicas significativas e acredita-se que seja desprovido de qualquer atividade nos receptores de dopamina, serotonina ou histamina. Não é viciante e a tolerância geralmente não se desenvolve. No entanto, a tolerância pode se desenvolver em alguns casos.

A ziconotida, um bloqueador dos potentes canais de cálcio controlados por voltagem do tipo N, é administrada por via intratecal para o alívio da dor intensa, geralmente relacionada ao câncer.

Adjuvantes

Certos medicamentos que foram introduzidos para usos diferentes dos analgésicos também são usados no tratamento da dor. Tanto os antidepressivos de primeira geração (como a amitriptilina) quanto os mais novos (como a duloxetina) são usados juntamente com AINEs e opioides para dor envolvendo danos nos nervos e problemas semelhantes. Outros agentes potencializam diretamente os efeitos dos analgésicos, como o uso de hidroxizina, prometazina, carisoprodol ou tripelenamina para aumentar a capacidade analgésica de uma determinada dose de analgésico opioide.

Analgésicos adjuvantes, também chamados de analgésicos atípicos, incluem orfenadrina, mexiletina, pregabalina, gabapentina, ciclobenzaprina, hioscina (escopolamina) e outras drogas com propriedades anticonvulsivantes, anticolinérgicas e/ou antiespasmódicas, bem como muitas outras drogas com ações no SNC. Essas drogas são utilizadas em conjunto com analgésicos para modular e/ou modificar a ação dos opioides quando usados contra a dor, principalmente de origem neuropática.

Observou-se que o dextrometorfano retarda o desenvolvimento e reverte a tolerância aos opioides, bem como exerce analgesia adicional ao agir sobre os receptores NMDA, assim como a cetamina. Alguns analgésicos, como a metadona e a cetobemidona e talvez a piritramida, têm ação NMDA intrínseca.

O licor com alto teor alcoólico, duas formas das quais foram encontradas na Farmacopeia dos EUA até 1916 e em uso comum por médicos até a década de 1930, foi usado no passado como um agente para aliviar a dor, devido ao depressor do SNC efeitos do álcool etílico, um exemplo notável sendo a Guerra Civil Americana. No entanto, a capacidade do álcool para aliviar a dor intensa é provavelmente inferior a muitos analgésicos usados hoje (por exemplo, morfina, codeína). Como tal, em geral, a ideia de álcool para analgesia é considerada uma prática primitiva em praticamente todos os países industrializados hoje.

O anticonvulsivante carbamazepina é usado para tratar a dor neuropática. Da mesma forma, os gabapentinóides gabapentina e pregabalina são prescritos para dor neuropática, e phenibut está disponível sem receita. Os gabapentinoides funcionam como bloqueadores da subunidade α2δ dos canais de cálcio controlados por voltagem e tendem a ter outros mecanismos de ação também. Os gabapentinoides são todos anticonvulsivantes, mais comumente usados para dor neuropática, pois seu mecanismo de ação tende a inibir a sensação de dor originada no sistema nervoso.

Outros usos

Analgesia tópica é geralmente recomendada para evitar efeitos colaterais sistêmicos. Articulações doloridas, por exemplo, podem ser tratadas com um gel contendo ibuprofeno ou diclofenaco (a bula do diclofenaco tópico foi atualizada para alertar sobre a hepatotoxicidade induzida por drogas.); a capsaicina também é usada topicamente. A lidocaína, um anestésico e esteróides podem ser injetados nas articulações para alívio da dor a longo prazo. A lidocaína também é usada para feridas dolorosas na boca e para anestesiar áreas para trabalhos dentários e pequenos procedimentos médicos. Em fevereiro de 2007, o FDA notificou os consumidores e profissionais de saúde sobre os perigos potenciais dos anestésicos tópicos que entram na corrente sanguínea quando aplicados em grandes doses na pele sem supervisão médica. Esses anestésicos tópicos contêm drogas anestésicas como lidocaína, tetracaína, benzocaína e prilocaína em creme, pomada ou gel.

Usos

Os anti-inflamatórios não esteróides tópicos fornecem alívio da dor em condições comuns, como entorses musculares e lesões por uso excessivo. Como os efeitos colaterais também são menores, as preparações tópicas podem ser preferidas aos medicamentos orais nessas condições.

Lista de medicamentos com comparação

Comparison of different analgesics

Generic name (INN)	Physicochemistry	Mechanism of action	Routes of administration	Pharmacokinetics	Indications	Major safety concerns
Nonsteroidal anti-inflammatory drugs
Unselective agents
Aceclofenac	Comes in betadex salt and free acid forms; practically insoluble in water, soluble in many organic solvents; degrades on contact with light; phenylacetic acid derivative.	As per diclofenac.	Oral (PO.)	Protein binding > 99%; half-life = 4 hours; metabolised to diclofenac (minor); excretion = urine (67%).	As per diclofenac.	As per diclofenac.
Acemetacin	Comes in free form; practically insoluble in water, soluble in certain organic solvents; degrades upon contact with light. Chemically related to indometacin	As per diclofenac.	PO.	Slightly metabolised to indometacin.	Rheumatoid arthritis, osteoarthritis and lower back pain.	As per diclofenac.
Amfenac	No available data.	As per diclofenac.	PO.	No data.	Pain and inflammation.	As diclofenac.
Aminophenazone	Related to phenylbutazone.	As per diclofenac.	PO.	Not available.	Musculoskeletal and joint disorders.	Agranulocytosis and cancer.
Ampiroxicam	Related to piroxicam.	As per diclofenac.	PO.	No data.	Rheumatoid arthritis and osteoarthritis.	Photosensitivity and other AEs typical of NSAIDs.
Amtolmetin guacil	Prodrug to tolmetin.	As per diclofenac.	PO.	No data.	As per diclofenac.	As per diclofenac.
Aspirin	Comes in free form, aluminium and lysine salt forms; fairly insoluble in water (1 in 300); highly soluble (1 in 5) in alcohol; degrades on contact with air. Salicylate.	Irreversibly inhibits COX-1 and COX-2; hence inhibiting prostaglandin synthesis.	PO, IM, IV, rectal	Bioavailability = 80–100%; protein binding = 25–95% (inversely dependent on plasma concentration); half life = 2–3 hours, 15–30 hours (higher doses); excretion = 80–100%.	Blood thinning; mild-to-moderate pain; fever; rheumatic fever; migraine; rheumatoid arthritis; Kawasaki's disease	GI bleeds; ulcers; Reye syndrome; nephrotoxicity; blood dyscrasias (rarely); Stevens–Johnson syndrome (uncommon/rare)
Azapropazone	Comes in free form; fairly insoluble in water and chloroform, soluble in ethanol; phenylbutazone.	As per diclofenac.	PO, rectal.	No data available.	Rheumatoid arthritis; gout; ankylosing spondylitis.	As per diclofenac.
Bendazac	Comes in free acid and lysine salt forms. Chemically related to indometacin.	As per acetametacin.	Topical, ophthalmologic.	N/A	Skin conditions (such as contact dermatitis) and 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 per diclofenac.	Topical, PO, rectal, spray and vaginal.	No data available.	Musculoskeletal disorders; soft-tissue disorders; sore throat.	As per diclofenac.
Bromfenac	Comes in free acid form; phenylacetic acid derivative.	Reversible COX-1/COX-2 inhibitor.	Ophthalmologic.	N/A	Postoperative pain and inflammation.	Corneal ulceration.
Bufexamac	Comes in free acid form; practically insoluble in water, soluble in a few organic solvents; degrades upon contact with light.	Reversible COX-1/COX-2 inhibition.	Topical.	No data.	Skin disorders.	Skin conditions, such as contact dermatitis.
Carbasalate	Comes in calcium salt form; fairly soluble in water.	Is metabolised to aspirin and urea. As per aspirin.	Oral.	No data.	Used for thromboembolic disorders.	As per diclofenac.
Clonixin	Comes in free acid and lysine salt forms.	Reversible COX-1/COX-2 inhibition.	PO, IM, IV, rectal.	No data.	Pain.	As per diclofenac.
Dexibuprofen	D-isomer of ibuprofen. Propionic acid derivative.	As per diclofenac.	PO.	Bioavailability = ?; protein binding = 99%; metabolism = hepatic via carboxylation and hydroxylation; half-life = 1.8–3.5 hours; excretion = Urine (90%).	Osteoarthritis; mild-moderate pain and menstrual pain.	As per diclofenac.
Diclofenac	Comes in sodium, potassium and diethylamine (topically used as a gel) salt forms; sparingly soluble in water but soluble in ethanol. Unstable in the presence of light and air. Indole acetic acid derivative.	Reversible COX-1/COX-2 inhibitor.	PO and topical.	Bioavailability = 50–60%; protein binding = 99–99.8%; hepatic metabolism; half-life = 1.2–2 hours; excretion = urine (50–70%), faeces (30–35%)	Rheumatoid arthritis; osteoarthritis; inflammatory pain (e.g. period pain); local pain/inflammation (as a gel); actinic keratoses; heavy menstrual bleeding	As per aspirin, except without Reye syndrome and with the following additions: myocardial infarctions, strokes and hypertension. More prone to causing these AEs compared to the other non-selective NSAIDs.
Diethylamine salicylate	Freely soluble in water; degrades upon contact with light and iron.	As per diclofenac.	Topical.	N/A.	Rheumatic and musculoskeletal pain.	As per bufexamac.
Diflunisal	Comes in free acid and arginine salt forms; practically insoluble in water, soluble in ethanol; degrades upon contact with light.	As per diclofenac.	PO, IM, IV.	Bioavailability = 80–100%; protein binding > 99%; volume of distribution = 0.11 L/kg; hepatic metabolism; half-life = 8–12 hours; excretion = urine (90%), faeces (<5%).	Pain; osteoarthritis; rheumatoid arthritis.	As per diclofenac.
Epirizole	Comes in free form.	As per diclofenac.	PO.	Not available.	Rheumatoid arthritis.	As per diclofenac.
Ethenzamide	Comes in free form; salicylate.	As per diclofenac.	PO.	Not available.	Musculoskeletal pain; fever.	As per diclofenac.
Etofenamate	Liquid; practically insoluble in water, miscible with ethyl acetate and methanol.	As per diclofenac.	Topical.	Not available.	Musculoskeletal, joint and soft-tissue disorders.	As per bufexamac.
Felbinac	Comes in free and diisopropanolamine salt forms; practically insoluble in water and ethanol, soluble in methanol.	As per diclofenac.	Topical.	N/A	Musculoskeletal pain and soft tissue injuries.	As per bufexamac.
Fenbufen	Comes as free acid; fairly insoluble in most solvents (including water); propionic acid derivative.	As per diclofenac.	PO.	Protein binding > 99%; half-life = 10–17 hours.	As per diclofenac.	As per diclofenac.
Fenoprofen	Comes in calcium salt; fairly insoluble in water and chloroform and fairly soluble in alcohol; sensitive to degradation by air. Propionic acid derivative.	As per diclofenac.	PO.	Bioavailability = ?; protein binding = 99%; hepatic metabolism; excretion = urine, faeces.	Pain; rheumatoid arthritis and osteoarthritis.	As per diclofenac.
Fentiazac	Comes in free form and calcium salt; acetic acid derivative.	As per diclofenac.	PO.	No data.	As per diclofenac.	As per diclofenac.
Fepradinol	Comes in free acid and hydrochloride salt forms.	As per diclofenac.	Topical.	N/A	Local inflammatory response.	As per bufexamac.
Feprazone	Comes in free acid and piperazine salt forms. Phenylbutazone.	As per diclofenac.	PO, Rectal, topical.	Not available.	As per diclofenac.	As per bufexamac (topical use) and diclofenac (PO/rectal).
Floctafenine	Comes in free acid form; anthranilic acid derivative.	As per diclofenac.	Oral.	Extensively metabolised by the liver; half-life = 8 hours; excretion = urinary and biliary.	Short-term relief from pain.	As per diclofenac.
Flufenamic acid	Comes in free acid form and aluminium salt form; anthranilic acid.	As per diclofenac.	Topical.	N/A	Soft tissue inflammation and pain.	As per bufexamac.
Flurbiprofen	Comes in sodium salt and free acid forms; fairly insoluble in water but soluble in ethanol; sensitive to degradation by air. Propionic acid derivative.	As per diclofenac.	PO, IM, IV, ophthalmologic.	Bioavailability = 96% (oral); protein binding > 99%; volume of distribution = 0.12 L/kg; excretion = urine (70%).	Ophthalmologic: Vernal keratoconjunctivitis; postoperative ocular swelling; herpetic stromal keratitis, excimer laser photorefractive keratectomy; ocular gingivitis. Systemic use: rheumatoid arthritis; osteoarthritis.	As per bromfenac (ophthalmologic) and diclofenac (PO/IM/IV).
Glucametacin	Indometacin derivative.	As per diclofenac.	PO.	Not available.	Musculoskeletal, joint, peri-articular and soft-tissue disorders.	As per diclofenac.
Ibuprofen	Comes in lysine salt and free acid forms; practically insoluble in water, but soluble in ethanol, acetone, methanol, dichloromethane and chloroform. Degrades in the presence of air. Propionic acid derivative.	As per diclofenac.	PO, IV, topical	Bioavailability = 80–100%; protein binding = 90–99%; hepatic metabolism, mostly via CYP2C9 and CYP2C19-mediated oxidation; excretion = Urine (50–60%), faeces.	Pain; fever; inflammatory illness; rheumatoid arthritis; osteoarthritis; heavy menstrual bleeding; patent ductus arteriosus.	As per diclofenac, except with lower risk of myocardial infarction, stroke and hypertension.
Imidazole salicylate	Comes in free form. Salicylate.	As per diclofenac.	PO, rectal, topical.	Not available.	Muscular and rheumatic pain.	As per bufexamac (topical use) and diclofenac (PO/rectal).
Indometacin	Comes in free acid and sodium salt forms; practically insoluble in water and most solvents; sensitive to degradation by light. Acetic acid derivative.	As per diclofenac.	PO, IV, rectal	Bioavailability = 100% (oral); protein binding = 90%; hepatic metabolism; excretion = urine (60%), faeces (33%).	Rheumatoid arthritis; osteoarthritis; gout; ankylosing spondylitis; period pain; patent ductus arteriosus.	As per diclofenac.
Isonixin	Comes in free form.	As per diclofenac.	PO, rectal and topical.	Not available.	Musculoskeletal and joint disorders.	As per bufexamac (topical use) and diclofenac (PO/rectal).
Kebuzone	Comes in free and sodium salt form; phenylbutazone derivative.	As per diclofenac.	IM, PO.	Not available.	As per diclofenac.	As per diclofenac.
Ketoprofen	Comes in free acid, lysine salt, sodium salt and hydrochloride salt forms; the dex-enantiomer comes in trometamol salt form. Practically insoluble in water; freely soluble in most other solvents. Propionic acid derivative.	As per diclofenac.	PO, rectal, topical, transdermal, intravenous, intramuscular.	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).	Rheumatoid arthritis, osteoarthritis and superficial sporting injuries (topical use).	As per diclofenac.
Ketorolac	Comes in the trometamol salt form; highly soluble in water. Degrades in the presence of light. Acetic acid derivative.	As per diclofenac.	PO, IM, IV, intranasal, tromethamine and ophthalmologic.	Bioavailability of IM formulation = 100%; protein binding = 99%; hepatic metabolism mostly via glucoronic acid conjugation and p-hydroxylation; half-life = 5–6 hours; excretion = urine (91.4%), faeces (6.1%).	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.	As per diclofenac.
Lornoxicam	Hydrochloride salt form used; oxicam derivative.	As per diclofenac.	PO.	Protein binding = 99%; volume of distribution = 0.2 L/kg; half-life = 3–5 hours; excretion = faeces (51%), urine (42%).	Acute and chronic pain.	As per diclofenac.
Loxoprofen	Comes in sodium salt form. Propionic acid derivative.	As per diclofenac.	Topical.	N/A	Local inflammation and pain.	As per diclofenac.
Magnesium salicylate	Comes in free form; soluble in water and ethanol; salicylate.	As per diclofenac.	PO.	Not available.	As per diclofenac.	As per diclofenac.
Meclofenamic acid	Comes in free acid and sodium salt form, sodium salt is the form used in human medicine; practically insoluble in water (free acid) and freely soluble in water (sodium salt); sensitive to degradation by air and light.	As per diclofenac.	PO.	Protein binding > 99%; half-life = 2–4 hours; hepatically metabolised via oxidation, hydroxylation, dehalogenation and conjugation with glucuronic acid; excretion = urine, faeces (20–30%).	Osteoarthritis; rheumatoid arthritis; mild-moderate pain; dysmenorrhoea; menorrhagia.	As per diclofenac.
Mefenamic acid	Comes in free acid form; practically insoluble in water, fairly insoluble in organic solvents; degrades on contact with air and light. Anthranilic acid derivative.	As per diclofenac.	PO.	Protein binding extensive; hepatic metabolism, mostly via CYP2C9; half-life = 2 hours; excretion = urine (66%), faeces (20–25%).	Inflammatory pain and heavy menstrual bleeding.	As per diclofenac.
Mofezolac	Comes in free form.	As per diclofenac.	PO.	Not available.	Musculoskeletal and joint pain.	As per diclofenac.
Morniflumate	Comes in free acid form; niflumic acid derivative.	As per diclofenac.	PO, rectal.	Not available.	Inflammatory conditions.	As per diclofenac.
Nabumetone	Comes in free acid form; practically insoluble in water, freely soluble in acetone; degrades on contact with air and light.	As per diclofenac.	PO.	Protein binding = 99%; hepatically metabolised; half-life = 24 hours; excretion = urine (80%), faeces (9%).	Osteoarthritis; rheumatoid arthritis.	As per diclofenac.
Naproxen	Comes in free acid and sodium form; practically insoluble in water in free form, freely soluble in water (sodium salt), fairly soluble in most organic solvents. Degrades on contact with air and light. Propionic acid derivative.	As per diclofenac.	PO.	Bioavailability = ?; protein binding > 99.5%; volume of distribution = 10% of bodyweight; half-life = 12–15 hours; excretion = urine (95%), faeces (<3%).	Rheumatoid arthritis; osteoarthritis; ankylosing spondylitis; juvenile idiopathic arthritis; inflammatory pain; heavy menstrual bleeding.	As per diclofenac. less prone to causing thrombotic events compared to other non-selective NSAIDs.
Nepafenac	Comes in free form; related to amfenac.	As per diclofenac.	Ophthalmologic.	Unavailable.	Inflammation and pain following cataract surgery.	As per bromfenac.
Niflumic acid	Comes in free acid form, glycinamide and ethyl ester form; practically insoluble in water, soluble in ethanol, acetone and methanol. Nicotinic acid derivative.	As per diclofenac.	PO, rectal (ethyl ester, morniflumate).	Unavailable.	Musculoskeletal, joint and mouth inflammatory disorders.	As per diclofenac.
Oxaprozin	Comes in potassium and free acid forms; degrades upon contact with light. Propionic acid derivative.	As per diclofenac.	PO.	Bioavailability = ?; protein binding > 99.5%; volume of distribution = 0.15–0.25 L/kg; half-life = 50–60 hours; excretion = urine (65), faeces (35%).	Osteoarthritis; rheumatoid arthritis.	As per diclofenac.
Oxyphenbutazone	Comes in free form. Phenylbutazone.	As per diclofenac.	PO, Ophthalmologic.	Unavailable.	Ophthalmologic: Episcleritis. Systemic (now seldom used due to adverse effects): ankylosing spondylitis; rheumatoid arthritis; osteoarthritis.	As per bromfenac. For systemic use haematological side effects such as aplastic anaemia; agranulocytosis; leucopenia; neutropenia; etc.
Phenazone	No data.	As per diclofenac.	PO, otolaryngologic.	Protein binding < 10%; half-life = 12 hours; hepatic metabolised; excretion = urine (primary), faeces.	Acute otitis media.	Nephrotoxicity and haematologic toxicity and other AEs typical of NSAIDs.
Phenylbutazone	Comes in free form; practically insoluble in water, freely soluble in most organic solvents; degrades upon contact with light and air.	As per diclofenac.	PO, rectal, topical.	No data available.	Ankylosing spondylitis; acute gout; osteoarthritis; rheumatoid arthritis.	Haematologic toxicity (including agranulocytosis, aplastic anaemia) and AEs typical of NSAIDs.
Piketoprofen	Comes in free form.	As per diclofenac.	Topical.	N/A.	Musculoskeletal, joint, peri-articular and soft-tissue disorders.	As per other topical NSAIDs.
Piroxicam	Comes in free acid and betadex salt forms; practically insoluble in water, slightly soluble in ethanol; degrades on contact with air and light. Enolic acid derivative.	As per diclofenac.	PO, topical.	Protein binding = 99%; extensively hepatically metabolised; half-life = 36–45 hours; excretion = urine, faeces.	Rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and sports injuries (topical use).	As per diclofenac.
Proglumetacin	Comes in maleate salt form; indometacin derivative.	As per diclofenac.	PO, rectal, topical.	Not available.	Musculoskeletal and joint disorders.	As per diclofenac.
Proquazone	Comes in free form.	As per diclofenac.	PO, rectal.	Not available.	As per diclofenac.	As per diclofenac.
Pranoprofen	No data.	As per diclofenac.	PO, ophthalmologic.	Not available.	Pain, inflammation and fever.	As per diclofenac.
Salamidacetic acid	Comes in sodium and diethylamine salt forms; salicylate.	As per diclofenac.	PO.	Unavailable.	Musculoskeletal disorders.	As per diclofenac.
Salicylamide	Fairly insoluble in water and chloroform; soluble in most other organic solvents; salicylate.	As per diclofenac.	PO, topical.	No data.	Muscular and rheumatic diseases.	As per diclofenac.
Salol	No data.	As per diclofenac.	PO, topical.	No data.	Lower urinary tract infections.	As per diclofenac.
Salsalate	Degrades upon contact with air; salicylate derivative.	As per diclofenac.	PO.	Hepatic metabolism; half-life = 7–8 hours; excretion = urine.	Rheumatoid arthritis, osteoarthritis.	As per diclofenac.
Sodium salicylate	Freely soluble in water; degrades upon contact with air and light; salicylate.	As per diclofenac.	PO, IV, topical.	No data.	Pain, fever and rheumatic conditions.	Cardiac problems; otherwise As per diclofenac.
Sulindac	Comes in free acid and sodium salt forms; practically insoluble in water and hexane, very slightly soluble in most organic solvents. Degrades upon contact with light. Acetic acid derivative.	As per diclofenac.	PO, rectal.	Bioavailability = 90%; protein binding = 93% (sulindac), 98% (active metabolite); hepatic metabolism; excretion = urine (50%), faeces (25%).	Rheumatoid arthritis; osteoarthritis; gout; ankylosing spondylitis; inflammatory pain.	As per diclofenac.
Suxibuzone	Practically insoluble in water, soluble in ethanol and acetone; phenylbutazone.	As per diclofenac.	PO, topical.	No data.	Musculoskeletal and joint disorders.	As per phenylbutazone.
Tenoxicam	Comes as free acid; practically insoluble in water, fairly insoluble in organic solvents; degrades upon contact with light.	As per diclofenac.	PO, rectal.	Bioavailability = 100% (oral), 80% (rectal); protein binding = 99%; volume of distribution = 0.15 L/kg; half-life = 60–75 hours; excretion = urine (67%), faeces (33%).	Osteoarthritis; rheumatoid arthritis; soft tissue injury.	As per diclofenac.
Tetridamine	No data.	As per diclofenac.	Vaginal.	No data.	Vaginitis.	As per diclofenac.
Tiaprofenic acid	Comes as free acid; practically insoluble in water but freely soluble in most organic solvents; propionic acid derivative; degrades upon contact with light. Propionic acid derivative.	As per diclofenac.	PO.	Protein binding > 99%; volume of distribution = 0.1–0.2 L/kg; hepatic metabolism; half-life = 2–4 hours.	Ankylosing spondylitis; osteoarthritis; rheumatoid arthritis; fibrosis; capsulitis; soft-tissue disorders.	As per diclofenac.
Tiaramide	No data.	As per diclofenac.	PO.	No data.	Pain; inflammation.	As per diclofenac.
Tinoridine	No data.	As per diclofenac.	No data.	No data.	Pain; inflammation.	As per diclofenac.
Tolfenamic acid	Comes as free acid; practically insoluble in water; degrades upon contact with light; anthranilic acid.	As per diclofenac.	PO.	Protein binding = 99%; half-life = 2 hours; hepatically metabolised; excretion = urine (90%), faeces.	Migraine; osteoarthritis; rheumatoid arthritis; dysmenorrhoea.	As per diclofenac.
Tolmetin	Comes in sodium salt form; freely soluble in water, slightly soluble in ethanol, freely soluble in methanol. Acetic acid derivative.	As per diclofenac.	PO.	Protein binding > 99%; volume of distribution = 7–10 L; half-life = 1 hour; excretion = urine (90%).	Osteoarthritis; rheumatoid arthritis.	As per diclofenac.
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%).	Rheumatoid arthritis; osteoarthritis; ankylosing spondylitis; pain due to dysmenorrhoea or injury.	As per non-selective NSAIDs. More prone to causing thrombotic events than most of them, however, except diclofenac.
Etodolac	Comes in free form; practically insoluble in water, freely soluble in acetone and dehydrated alcohol. Acetic acid derivative.	As per celecoxib.	PO.	Bioavailability = ?; protein binding > 99%; volume of distribution = 0.41 L/kg; half-life = 6–7 hours; excretion = urine (73%).	Rheumatoid arthritis, including juvenile idiopathic arthritis; osteoarthritis; acute pain.	As per diclofenac.
Etoricoxib	Comes in free form; sulfonamide.	As per celecoxib.	PO.	Bioavailability = 100%; protein binding = 91.4%; volume of distribution = 120 L; half-life = 22 hours; hepatic metabolism; excretion = urine (70%), faeces (20%).	Acute pain; gout; osteoarthritis.	As per diclofenac.
Lumiracoxib†	Comes in free form; acetic acid derivative.	As per celecoxib.	PO.	Bioavailability = 74%; protein binding > 98%; extensive hepatic metabolism, mostly via CYP2C9; half-life = 3–6 hours; excretion = Urine (50%), faeces (50%).	Osteoarthritis.	As above, plus hepatotoxicity.
Meloxicam	Comes in free form; fairly insoluble in water and in most organic solvents; oxicam derivative.	As per celecoxib.	PO, rectal.	Bioavailability = 89%; protein binding > 99%; volume of distribution = 0.1–0.2 L/kg; half-life = 22–24 hours; extensive hepatic metabolism; excretion = urine (45%), faeces (47%).	Osteoarthritis; rheumatoid arthritis.	As per diclofenac.
Nimesulide	Comes in free and betadex form; practically insoluble in water and ethanol, soluble in acetone.	As per celecoxib.	PO, rectal, topical.	Unavailable.	Acute pain; dysmenorrhoea; sprains (topical); tendinitis.	As per diclofenac.
Parecoxib	Comes in sodium salt form; sulfonamide.	As per celecoxib.	IM, IV.	Plasma binding = 98%; volume of distribution = 55 L; hepatic metabolism, mostly via CYP2C9, CYP3A4; half-life = 8 hours; excretion = urine (70%).	Postoperative pain.	As per diclofenac.
Rofecoxib†	Comes in free form; sulfonamide.	As per celecoxib.	PO.	Bioavailability = 93%; protein binding = 87%; hepatic metabolism; half-life = 17 hours.	Acute pain; osteoarthritis; rheumatoid arthritis.	As per diclofenac.
Valdecoxib†	Comes in free form; sulfonamide.	As per celecoxib.	PO.	Bioavailability = 83%; protein binding = 98%; hepatic metabolism, mostly via CYP3A4 and CYP2C9; half-life = 8.11 hours; excretion = urine (90%).	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.	Opioid dependence, moderate-severe pain.	As per codeine, respiratory effects are subject to a ceiling effect.
Codeine	Comes in free form, hydrochloride salt, sulfate salt and phosphate salts; soluble in boiling water (free form), freely soluble in ethanol (free form), soluble/freely soluble in water (salt forms); sensitive to degradation by light. Methoxy analogue of morphine.	Metabolised to morphine, which activates the opioid receptors.	PO, IM, IV.	Extensive hepatic metabolism, mostly via CYP2D6, to morphine; half-life = 3–4 hours; excretion = urine (86%).	Mild-moderate pain, often in combination with paracetamol or ibuprofen.	Constipation, dependence, sedation, itching, nausea, vomiting and respiratory depression.
Diamorphine	Comes in hydrochloride salt form; freely soluble in water, soluble in alcohol; degrades upon contact with light. Diacetyl derivative of morphine.	Rapidly hydrolysed to 6-acetylmorphine and then to morphine after crossing the blood-brain barrier which in turn activates the opioid receptors in the CNS.	IM, intrathecal, intranasal, PO, IV, SC.	Extensively metabolised to morphine with 6-acetylmorphine as a possible intermediate. Mostly excreted in urine.	Severe pain (including labour pain); cough due to terminal lung cancer; angina; left ventricular failure.	As per codeine. Higher potential for abuse compared to other opioids due to its rapid penetration of the blood-brain barrier.
Dihydrocodeine	Comes in freebase, hydrochloride, phosphate, polistirex, thiocyanate, tartrate, bitartrate and hydrogen tartrate salt forms; freely soluble in water, practically insoluble in organic solvents (hydrogen tartrate salt); degrades upon contact with air and light.	Opioid receptor agonist.	IM, IV, PO, SC.	Bioavailability = 20%; extensive hepatic metabolism, partly via CYP2D6 to dihydromorphine and CYP3A4 to nordihydrocodeine; half-life = 3.5 –5 hours; excretion = urine.	Moderate-severe pain; usually in combination with paracetamol and/or aspirin.	As per codeine.
Ethylmorphine	Comes in freebase, hydrochloride, camphorate and camsilate salt forms; soluble in water and alcohol; degrades upon contact with light.	Opioid receptor ligand.	PO.	No data.	Cough suppressant.	As per codeine.
Hydrocodone	Comes in hydrochloride/tartrate salt form; freely soluble in water, practically insoluble in most organic solvents; degrades upon contact with light/air.	Opioid receptor ligand.	PO.	Protein binding = 19%; extensively hepatically metabolised, mostly via CYP3A4, but via CYP2D6 to a lesser extent to hydromorphone; half-life = 8 hours; excretion = urine.	Chronic pain.	As per codeine.
Hydromorphone	Comes in hydrochloride salt form; freely soluble in water, fairly insoluble in organic solvents; degrades upon contact with light or temperatures outside 15 °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.	Moderate-severe pain; cough.	As per codeine.
Morphine	Comes in freebase form, hydrochloride salt, sulfate salt and tartrate salt forms; soluble in water; degrades in the presence of light.	Opioid receptor agonist (μ, δ, κ).	IM, intrathecal, PO, IV, SC, rectal.	Protein binding = 35%; extensive hepatic metabolism, with some metabolism occur in the gut after oral administration; half-life = 2 hours; excretion = urine (90%).	Moderate-severe pain.	As per codeine.
Nicomorphine	Dinicotinic acid ester derivative of morphine.	As per morphine.	IM, IV, PO, rectal, SC.	No available data.	Moderate-severe pain.	As per codeine.
Oxycodone	Comes in freebase, hydrochloride and terephthalate salt forms; freely soluble in water and practically insoluble in organic solvents; degrades upon contact with air.	Opioid receptor agonist.	PO.	Bioavailability = 60–87%; protein binding = 45%; volume of distribution = 2.6 L/kg; extensively metabolised in the liver via CYP3A4 and to a lesser extent via CYP2D6 to oxymorphone; half-life = 2–4 hours; excretion = urine (83%).	Moderate-severe pain.	As per codeine.
Oxymorphone	Comes in hydrochloride salt form; fairly soluble in water (1 in 4), practically insoluble in most organic solvents; degrades upon contact with air, light and temperatures outside 15 °C to 30 °C.	As per morphine.	PO, IM, SC.	Bioavailability = 10% (oral); protein binding = 10–12%; volume of distribution = 1.94–4.22 L/kg; hepatic metabolism; half-life = 7–9 hours, 9–11 hours (XR); excretion = urine, faeces.	Postoperative analgesia/anaesthesia; moderate-severe pain.	As per codeine.
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.	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.	PO, IM, IV, SC.	Protein binding = 40%; extensive first-pass metabolism; half-life = 12–16 hours, 30 hours (repeated dosing).	Acute/chronic pain.	As per codeine.
Nalbuphine	Comes primarily as its hydrochloride salt.	Full agonist at kappa opioid receptors, partial agonist/antagonist at the mu opioid receptors.	IM, IV, SC.	Protein binding = not significant; hepatic metabolism; half-life = 5 hours; excretion = urine, faeces.	Pain; anaesthesia supplement; opioid-induced pruritus.	As per codeine. 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 per codeine.
Eptazocine	Comes as hydrobromide salt.	As per morphine.	IM, SC.	No data.	Moderate-severe pain.	As per codeine.
Pentazocine	Comes in free, hydrochloride and lactate salt forms; fairly insoluble in water (1:30 or less), more soluble in ethanol and chloroform; degrades upon contact with air and light.	Kappa opioid receptor agonist; mu opioid receptor antagonist/partial agonist.	IM, IV, SC.	Bioavailability = 60–70%; protein binding = 60%; hepatic metabolism; half-life = 2–3 hours; excretion = urine (primary), faeces.	Moderate-severe pain.	As per codeine. 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 codeine.
Ketobemidone	Comes in hydrochloride salt form; freely soluble in water, soluble in ethanol and fairly insoluble in dichloromethane.	Mu opioid; NMDA antagonist.	PO, IM, IV, rectal.	Bioavailability = 34% (oral), 44% (rectal); half-life = 2–3.5 hours.	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).	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).	Mu opioid.	IM, IV, PO, rectal.	No data available.	Severe pain.	As per other opioids.
Dextropropoxyphene	Comes in free form, hydrochloride and napsilate salt forms; very soluble in water (HCl), practically insoluble in water (napsilate); degrades upon contact with light and air.	Mu opioid.	PO.	Protein binding = 80%; hepatic metabolism; half-life = 6–12 hours, 30–36 hours (active metabolite).	Mild-moderate pain.	As per other opioids, plus ECG changes.
Dipipanone	Comes in hydrochloride salt form; practically insoluble in water and ether, soluble in acetone and ethanol.	Mu opioid.	PO, often in combination with cyclizine.	Half-life = 20 hours.	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.	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.	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%).	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%).	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.	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.
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%).	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.
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.	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%).	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%).	Chronic pain.	CNS toxicity (abnormal gait, abnormal vision, memory problems, etc.); GI effects.
Where † indicates products that are no longer marketed.

Pesquisa

Alguns analgésicos novos e em investigação incluem bloqueadores de canal de sódio dependentes de voltagem seletivos de subtipo, como funapida e raxatrigina, bem como agentes multimodais, como ralfinamida.