An analgesic (also known as a painkiller) is any member of the group of drugs used to relieve pain (achieve analgesia). The word analgesic derives from Greek an- ("without") and algos ("pain"). Analgesic drugs act in various ways on the peripheral and central nervous systems; they include paracetamol (para-acetylaminophenol, also known in the US as acetaminophen), the non-steroidal anti-inflammatory drugs (NSAIDs) such as the salicylates, and opioid drugs such as morphine and tramadol.
In choosing analgesics, the severity and response to other medication determines the choice of agent; the WHO pain ladder, originally developed in cancer-related pain, is widely applied to find suitable drugs in a stepwise manner. The 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.
The exact mechanism of action of paracetamol/acetaminophen is uncertain, but it appears to be acting centrally. Aspirin and the other non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenases, leading to a decrease in prostaglandin production. This reduces pain and also inflammation (in contrast to paracetamol and the opioids).
Paracetamol has few side effects and is regarded as safe, although excessive doses can lead to fatal kidney and liver damage in the form of analgesic nephropathy and paracetamol hepatotoxicity, respectively. NSAIDs predispose to peptic ulcers, renal failure, allergic reactions, and occasionally hearing loss, and they can increase the risk of hemorrhage by affecting platelet function. The use of aspirin in children under 16 suffering from viral illness may contribute to Reye syndrome.
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 that most of the adverse effects of NSAIDs were mediated by blocking the COX1 (constitutive) enzyme, with the analgesic effects being mediated by the COX2 (inducible) enzyme. The COX2 inhibitors were thus developed to inhibit only the COX2 enzyme (traditional NSAIDs block both versions in general). These drugs (such as rofecoxib and celecoxib) are equally effective analgesics when compared with NSAIDs, but cause less gastrointestinal hemorrhage in particular. However, post-launch data indicated increased risk of cardiac and cerebrovascular events with these drugs due to an increased likelihood of clotting in the blood due to a decrease in the production of protoglandin around the platelets causing less clotting factor to be released, and rofecoxib was subsequently withdrawn from the market. The role for this class of drug is debated.
Morphine, the archetypal opioid, and various other substances (e.g. codeine, oxycodone, hydrocodone, diamorphine, pethidine) all exert a similar influence on the cerebral opioid receptor system. Tramadol and buprenorphine are thought to be partial agonists of the opioid receptors. Tramadol is structurally closer to venlafaxine than to codeine and delivers analgesia by not only delivering "opiate-like" effects (through mild agonism of the mu receptor) but also by acting as a weak but fast-acting serotonin and norepinephrine reuptake inhibitor. Nevertheless, dosing of all opioids may be limited by opioid toxicity (confusion, respiratory depression, myoclonic jerks and pinpoint pupils), seizures (Tramadol), but there is no dose ceiling in patients who tolerate this.
Opioids, while very effective analgesics, may have some unpleasant side-effects. Up to 1 in 3 patients starting morphine may experience nausea and vomiting (generally relieved by a short course of antiemetics). 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.
When used appropriately, opioids and similar narcotic analgesics are otherwise safe and effective, however risks such as addiction and the body becoming used to the drug (tolerance) can occur. The effect of tolerance means that drug dosing may have to be increased if for a chronic disease. In toxicity tolerant patients, there is no ceiling limit for the drug. However, though there is no upper limit, toxic doses are possible even if the body has become accustomed to higher doses.
In patients with chronic or neuropathic pain, various other substances may have analgesic properties. Tricyclic antidepressants, especially 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 decrease the firing of specific nerve systems.
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.
The use of paracetamol, as well as aspirin, ibuprofen, naproxen, and other NSAIDS concurrently with weak to mid-range opiates (up to about the hydrocodone level) has been shown to have beneficial synergistic effects by combatting pain at multiple sites of action—NSAIDs reduce inflammation which, in some cases, is the cause of the pain itself while opiates dull the perception of pain—thus, in cases of mild to moderate pain caused in part by inflammation, it is generally recommended that the two be prescribed together.
Topical analgesia is generally recommended to avoid systemic side-effects. Painful joints, for example, may be treated with an ibuprofen- or diclofenac-containing gel; 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.
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.  Other psychotropic analgesic agents include ketamine (an NMDA receptor antagonist), clonidine and other α2-adrenoreceptor agonists, and mexiletine and other local anaesthetic analogues.
Orphenadrine, cyclobenzaprine, scopolamine, atropine, gabapentin, first-generation antidepressants and other drugs possessing anticholinergic and/or antispasmodic properties are used in many cases along with analgesics to potentiate centrally acting analgesics such as opioids when used against pain especially of neuropathic origin and to modulate the effects of many other types of analgesics by action in the parasympathetic nervous system. 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 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 "kill pain" may be inferior to many analgesics used today (e.g. morphine, codeine). As such, the idea of alcohol for analgesia is generally 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, methylphenidate, caffeine, ephedrine, dextroamphetamine, and cocaine work against heavy sedation and may elevate mood in distressed patients as do the antidepressants. A well-accepted benefit of THC to chronic pain patients on opioids is its superior anti-nauseant action. Some think it would make more sense to use the synthetic THC capsule (trade name Marinol), which is administered orally. However, in patients suffering from nausea, the swallowing of the capsule itself may provoke vomiting. Likewise, the use of medicinal cannabis remains a debated issue.