Category:Analgesics

The relief of pain is among the oldest aims of medicine. Willow bark, rich in salicin, was used as a remedy for pain and fever by Sumerian and Egyptian healers more than three thousand years ago, and was later described by Greek and Roman physicians.^[1] In 1763 the English clergyman Edward Stone reported to the Royal Society on dried willow bark as a treatment for fever, the first such account in a Western medical journal, beginning the chain of investigation that would lead, more than a century later, to aspirin.^[1]

Analgesics, medicines used to relieve pain, do not form a single pharmacological class. They are conventionally grouped into several distinct families: the non-steroidal anti-inflammatory drugs, paracetamol (acetaminophen), the opioids, a group of adjuvant medicines used mainly for neuropathic pain, and the muscle relaxants, which relieve certain kinds of pain indirectly.

The use of pain-relieving plant materials is ancient, but the modern history of the salicylates begins with the investigation of willow bark. Following Edward Stone's 1763 report, salicin was isolated from willow bark in the early nineteenth century, and salicylic acid was derived from it.^[1]

Aspirin (acetylsalicylic acid) was first synthesized in an impure form by the French chemist Charles Frédéric Gerhardt in 1853, but he did not develop it. A stable, usable form was prepared by Felix Hoffmann at the Bayer company in 1897, and aspirin was marketed from 1899.^[1]

Paracetamol (also called acetaminophen) was first synthesized by Joseph von Mering in 1893, though it did not come into wide clinical use until the mid-twentieth century.^[2] It relieves pain and reduces fever but has little anti-inflammatory effect, and for that reason is generally not classed as an NSAID.

Through the twentieth century a large family of non-steroidal anti-inflammatory drugs (NSAIDs) was developed, including ibuprofen, naproxen, and diclofenac, alongside aspirin. A major advance in understanding came in the early 1970s, when John Vane and colleagues reported that aspirin and similar medicines inhibit the cyclooxygenase (COX) enzyme, reducing the synthesis of prostaglandins, signalling molecules involved in pain, fever, and inflammation. This work was later recognized with a Nobel Prize.^[3] Two principal forms of the enzyme, COX-1 and COX-2, were identified in the early 1990s.

The skeletal muscle relaxants relieve pain indirectly: rather than acting on pain-signalling pathways, they reduce painful muscle spasm or spasticity, and pain relief follows from that. They are conventionally divided into two groups.^[4]

Antispasmodics, including cyclobenzaprine, methocarbamol, carisoprodol, metaxalone, and chlorzoxazone, are used mainly for musculoskeletal conditions such as acute low back pain. Antispastics, including baclofen and dantrolene, are used for spasticity arising from neurological conditions such as multiple sclerosis and spinal cord injury. A few agents, such as tizanidine, are used in both roles.^[4]

Evidence for the antispasmodics in back pain has generally been limited to short-term relief, and systematic reviews have found the evidence for longer-term use insufficient.^[4]

The analgesic families are understood to relieve pain in different ways, and the strength of evidence behind these accounts varies. It is also worth noting a general caution: that a medicine binds a particular molecular target is one kind of claim; that this binding produces a given clinical effect is a separate inference, and the two are not always supported by evidence to the same degree.

NSAIDs are understood to relieve pain mainly by inhibiting COX enzymes and so reducing prostaglandin synthesis.^[3]

The mechanism of paracetamol is, by contrast, still debated. It is a weak inhibitor of COX-1 and COX-2 and its effect appears to be exerted mainly within the central nervous system; several explanations have been proposed, including a once-suggested "COX-3" variant and an action of its metabolite AM404, but no single account is currently established.^[2]

Opioids bind opioid receptors, especially the µ-opioid receptor, in the nervous system; the relationship between this binding and their analgesic and other effects is addressed in Category:Opioids. The skeletal muscle relaxants are a varied group whose mechanisms are not all well established; baclofen, for example, is understood to act at GABA receptors in the spinal cord, but the detail of its action as a muscle relaxant is described in the literature as incompletely understood.^[4] Adjuvant analgesics, including certain antidepressants and anticonvulsants, are used mainly for neuropathic pain.

The analgesics include the Category:NSAIDs (such as aspirin, ibuprofen, and naproxen), paracetamol (acetaminophen), the Category:Opioids (such as morphine, oxycodone, and fentanyl), and the Category:Muscle relaxants. Further agents are used for specific pain syndromes, including triptans, ergot derivatives, and gepants for migraine, and certain antidepressants and anticonvulsants as adjuvants for neuropathic pain. The list is not exhaustive.

Reported adverse effects differ markedly between the families, and figures in the literature are population estimates that vary between studies. NSAIDs are associated with gastrointestinal effects including ulceration and bleeding, with effects on kidney function, and with cardiovascular risk that varies by agent and dose. Paracetamol is generally well tolerated at recommended doses but is associated with serious liver injury in overdose. The muscle relaxants are commonly associated with sedation and dizziness; some, such as dantrolene, carry a warning regarding serious liver injury, and others, such as carisoprodol, have a recognized potential for dependence. The opioids carry distinct risks, including respiratory depression and the potential for dependence, and are discussed separately. Individual response and tolerability are reported to vary considerably between people.