Category:Non-opioid analgesics

A non-opioid analgesic is a medicine that relieves pain by a mechanism other than agonism at the opioid receptors. The category is heterogeneous by design: it includes the paracetamol group, the non-steroidal anti-inflammatory medicines whose action is the inhibition of prostaglandin synthesis, the gabapentinoids and certain antidepressants used in neuropathic pain, the topical agents (capsaicin, lidocaine patches), and the small number of newer agents acting on novel targets. The unifying feature is the absence of opioid-receptor pharmacology and so of the dependence, respiratory-depression, and tolerance liabilities that distinguish the opioid analgesics.

The clinical use of the willow bark for pain and fever is among the oldest documented in medicine, with references in the Edwin Smith papyrus of about 1500 BCE and in the writings of Hippocrates and Dioscorides. The pharmacological era opened with a letter from the Oxfordshire countryside. On 25 April 1763 the Reverend Edward Stone, rector of the parish of Chipping Norton, wrote to the Royal Society in London that powdered willow bark, given to fifty of his ague-ridden parishioners in doses of a dram every four hours, had cured them; the bark, he observed, was bitter, and the doctrine of signatures had led him to try it.^[1] The active principle was named salicin by Joseph Buchner in Munich in 1828 and converted to salicylic acid by Raffaele Piria in Pisa in 1838. Salicylic acid was effective but gastrointestinally toxic; the Strasbourg chemist Charles Gerhardt in 1853 reported the acetylation of salicylic acid to produce acetylsalicylic acid but did not pursue the compound. In 1897 the Bayer chemist Felix Hoffmann, working under Heinrich Dreser (the same chief chemist who would shortly market diacetylmorphine as Heroin), re-synthesised acetylsalicylic acid in pure form, and Bayer introduced it under the trade name Aspirin in 1899. It became the most widely used medicine of the twentieth century.

The mechanism by which aspirin worked remained unexplained for seventy years. In 1971 the British pharmacologist John Vane at the Royal College of Surgeons in London reported that aspirin, indomethacin, and salicylate inhibited the synthesis of prostaglandins from arachidonic acid in homogenates of guinea-pig lung;^[2] the prostaglandins were known to sensitise peripheral nociceptors and to mediate the inflammatory cascade, and the mechanism of an entire class of medicines fell into place. Vane shared the Nobel Prize in 1982 with Sune Bergström and Bengt Samuelsson for the broader work on the prostaglandins. The 1990s identification of two cyclo-oxygenase isoforms, COX-1 (constitutive, gastrically protective) and COX-2 (inducible, predominant in inflammation), by Daniel Simmons and Philip Needleman motivated the development of the selective COX-2 inhibitors: celecoxib (Pfizer, 1998), rofecoxib (Merck, 1999), and valdecoxib. Rofecoxib was withdrawn worldwide in 2004 after the VIGOR and APPROVe trials showed a small but consistent excess of myocardial infarction and stroke in patients on long-term treatment, a finding subsequently attributed to disturbance of the COX-2-mediated vascular endothelial prostaglandin I2 production.

The other dominant non-opioid analgesic, paracetamol (known as acetaminophen in the United States), arrived by a different route. In 1886 Arnold Cahn and Paul Hepp, two physicians at the medical clinic of Strasbourg, accidentally administered the industrial chemical acetanilide to a patient when an apothecary's error substituted it for naphthalene, intended as an anthelmintic; the patient's worms persisted but his fever resolved.^[3] Acetanilide, marketed as Antifebrin, was followed by Bayer's phenacetin in 1887, and both medicines were used widely as antipyretics and analgesics for the next sixty years; both also produced methaemoglobinaemia and, on long-term use, renal-papillary necrosis. In 1948 the National Institutes of Health pharmacologists Bernard Brodie and Julius Axelrod showed that the active analgesic metabolite of both acetanilide and phenacetin was a third compound, paracetamol, and that this metabolite was substantially less toxic than its precursors.^[4] McNeil Laboratories introduced paracetamol in the United States as Tylenol in 1955; the medicine has since become the most widely used analgesic in the world, with the important caveat that its hepatotoxicity in overdose, mediated by the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI), is a leading cause of acute liver failure in the developed world.

The chronic and neuropathic pain pharmacopoeia extended in a different direction in the last decades of the twentieth century. The tricyclic antidepressant amitriptyline was shown in 1965 by Woodforde to be effective in postherpetic neuralgia and trigeminal neuralgia, opening the long-running indication for tricyclic antidepressants in neuropathic pain that has since been formalised in clinical guidelines. The anticonvulsants carbamazepine (1962, originally for trigeminal neuralgia by Blom) and later gabapentin (Parke-Davis, 1993, approved for partial-onset seizures and subsequently for postherpetic neuralgia) and pregabalin (Pfizer, 2004) entered the pain pharmacopoeia as the gabapentinoids; their mechanism is binding to the α2δ subunit of voltage-gated calcium channels, reducing neurotransmitter release at central nociceptive terminals. The serotonin-noradrenaline reuptake inhibitor duloxetine (Eli Lilly, 2004), originally an antidepressant, was extended to diabetic peripheral neuropathy and to fibromyalgia. None of these medicines is an analgesic in the conventional acute-pain sense; their effect is in chronic neuropathic and centrally sensitised pain syndromes, where they reduce the pain intensity over weeks of regular use rather than within hours of a dose.

The topical and the locoregional medicines complete the category. Topical capsaicin (cream and the 8% high-concentration patch) acts on the TRPV1 receptor of cutaneous C-fibres to produce defunctionalization with prolonged use. Topical lidocaine and the lidocaine 5% patch act on peripheral sodium channels and are useful in localised neuropathic pain such as postherpetic neuralgia. The local anaesthetics, of which the prototype is the cocaine introduced by Carl Koller for ophthalmic surgery in 1884 and which has since extended through procaine (Einhorn, 1905), lidocaine (Löfgren, 1943), bupivacaine, and ropivacaine, are not principally analgesics in the systemic sense but they are central to perioperative pain management; they are listed under anesthetics.

The contemporary clinical position of the non-opioid analgesic is, in part, a reaction against the opioid epidemic. Where chronic non-cancer pain was, twenty years ago, often treated with long-term opioid prescription, current practice favours a non-opioid scaffold (paracetamol on a schedule, an NSAID where renal and cardiovascular safety permit, a gabapentinoid or antidepressant for neuropathic components, topical agents where the pain is localised) with opioid use reserved for short courses, for cancer pain, and for situations in which the alternatives have failed.

By mechanism:

• Paracetamol (acetaminophen): acetaminophen / paracetamol
• Non-steroidal anti-inflammatory medicines (non-selective COX inhibitors): aspirin, ibuprofen, naproxen, diclofenac, indomethacin, ketorolac, meloxicam (preferential COX-2)
• COX-2 selective inhibitors: celecoxib
• Gabapentinoids (α2δ voltage-gated calcium channel ligands, for neuropathic pain): gabapentin, pregabalin
• Tricyclic antidepressants for neuropathic pain: amitriptyline, nortriptyline, desipramine
• SNRIs for chronic pain: duloxetine, venlafaxine
• Topical: capsaicin cream and patch, lidocaine patch
• Other: ketamine (NMDA antagonist, in subanaesthetic doses for refractory pain), the alpha-2 agonists clonidine and dexmedetomidine (off-label adjuncts), the antimigraine triptans (collected separately under triptans)

The boundary of this category is "medicine prescribed for the relief of pain by a mechanism other than opioid-receptor agonism." The opioid analgesics are collected separately. The medicines used in the prophylaxis of migraine (migraine prophylaxis) and in the acute treatment of migraine (triptans, gepants, the calcitonin gene-related peptide antagonists) are listed under those specific indications, although they are non-opioid by mechanism. Local and regional anaesthetics, while they relieve pain, are collected under anesthetics when their indication is operative anesthesia and listed here only when their indication is analgesia (lidocaine patch in postherpetic neuralgia, intra-articular bupivacaine).

This category page is an encyclopedia article about its subject. The actual index of medicines belonging to the category is generated automatically by the wiki engine, from category-membership declarations on the individual medicine pages, and appears at the foot of the page below the references.