Analgesics: History, Uses, Categories, Examples, Safety

An Analgesic refers to any drug that relieves pain selectively without blocking the conduction of nerve impulses, markedly altering sensory perception, or affecting consciousness. This selectivity is an important distinction between an analgesic and an anesthetic.

The history of pain treatment likely started in the cradle of mankind, as the experience of pain from many causes presumably had an aversive dimension comparable in its ranking to elementary sensations and motivations. Advances in basic and clinical research have greatly expanded the options for analgesic pharmacotherapy. There are two broad categories of analgesic medications namely:

Non-opioid analgesics

Non-opioid analgesics encompass non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol (acetaminophen). The NSAIDs include acetylsalicylic acid (ASA, aspirin), dipyrone (metamizole), and numerous other drugs in diverse classes. The NSAIDs have potent anti-inflammatory, analgesic, and antipyretic activity, and are among the most widely used drugs worldwide. In palliative medicine, they represent the first step of the World Health Organization’s analgesic ladder used for mild pain and they are an important supplement to opioids and adjuvant drugs at higher steps of the ladder.

Most anti-inflammatory analgesics are derived from three compounds discovered in the 19th century—salicylic acid, pyrazolone, and phenacetin (or acetophenetidin). Although chemically unrelated, the drugs in these families have the ability to relieve mild to moderate pain through actions that reduce inflammation at its source. Acetylsalicylic acid, or aspirin, which is derived from salicylic acid, is the most widely used mild analgesic. It is considered the prototype for anti-inflammatory analgesics, the two other major types of which include acetaminophen (a derivative of phenacetin) and aspirin-like drugs, or nonsteroidal anti-inflammatory drugs (NSAIDs). Examples of anti-inflammatory analgesics include drugs such as ibuprofen (e.g. brand names Advil, Nuprin, Motrin), naproxen (e.g. brand names Aleve, Naprosyn), or prescription Cox-2 inhibitors (e.g. brand name Celebrex).

Differences Among Non-Opioid Analgesics

Acetaminophen. The analgesic and fever-reducing effects of acetaminophen are well-known, but its mechanism of action is not. Nevertheless, it is widely considered to be the safest analgesic available although the liver injury is a concern with overdose.

Aspirin and other NSAIDs. Aspirin and other NSAIDs alleviate pain and reduce fever and inflammation by decreasing the synthesis and release of prostaglandins, which are pro-inflammatory molecules. Cyclooxygenase-2 (COX-2) inhibitors also inhibit prostaglandin synthesis and release, but unlike aspirin and non-selective NSAIDs, COX-2 inhibitors do not inhibit platelet aggregation.

Antidepressants. Tricyclic antidepressants (amitriptyline) and serotonin-norepinephrine (noradrenaline) reuptake inhibitors (SNRIs, e.g., duloxetine) have unknown mechanisms for their pain-relieving properties. However, studies suggest that their analgesic effects may be related in part to presynaptic inhibition of the reuptake of serotonin and norepinephrine in pain inhibitory pathways, as well as a peripheral mechanism involving β2-adrenergic receptors.

Anticonvulsants. Anticonvulsive drugs (including gabapentin and pregabalin) provide analgesic properties by lowering neurotransmitter release or reducing neuronal firing.

Topical treatments. Topical non-opioid medications such as lidocaine and capsaicin are applied to the skin and thus act locally. Lidocaine works by blocking nerve signals that send the feeling of pain from the site of injury to the brain. It causes a temporary loss of feeling in the area to which it is applied. Capsaicin appears to deplete local neurons of substance P, which is required in the transmission of nociceptive input.

Opioid analgesics

These are drugs that in moderate doses dull the senses, relieve pain, and induce profound sleep but in excessive doses cause stupor, coma, or convulsions. Opioids have a narcotic effect; that is, they induce sedation and are effective for the management of many types of pain. Opioid receptors are found extensively in the brain and spinal cord, as well as in the vascular system, gut, lungs, airway, cardiac system, and some immune system cells.

There are at least three types of receptors on brain neurons that are activated by the enkephalins. Morphine and its congeners are thought to exert their effects by activating one or more of these receptors.

Opioid drugs are useful in the treatment of general postoperative pain, severe pain, and other specific conditions. The use of opioids to relieve the pain associated with kidney stones or gallstones presumably depends on their ability to affect opioid receptors in these tissues and inhibit contractility. By a similar mechanism, opioids are also able to relieve abdominal distress and fluid loss of diarrhea. Central receptors appear to account for the ability of morphine and analogs to suppress coughing, an effect that requires lower doses than those needed for analgesia. Low doses of opioids are also used for relief of the respiratory distress that accompanies acute cardiac insufficiency complicated by the buildup of fluid in the lungs.

Several commonly used natural or synthetic derivatives of morphine are used in drug therapeutics. Codeine, a naturally occurring opium alkaloid that can be made synthetically, is a useful oral analgesic, especially when used in combination with aspirin. Meperidine was an early synthetic analog of morphine, marketed under the trade name Demerol, that was originally thought to be able to provide significant short-lasting analgesia and little or no addiction because of its shortened duration of action; however, this belief proved false. Methadone, a synthetic opioid analgesic, has long-lasting analgesic effects (six to eight hours) when taken orally and is used to moderate the effects of withdrawal from heroin addiction. Among the opioid antagonist drugs, naloxone and its longer-lasting orally active version, naltrexone, are used primarily to reverse morphine overdoses and to reverse the chemical stupor of a wider variety of causes, including alcohol intoxication and anesthesia. In opioid overdoses, these drugs provide recovery within minutes of injection. They can, however, also precipitate severe withdrawal reactions in a person addicted to opiates.

The effectiveness of a given dose of an opioid drug declines with its repeated administration in the presence of intense pain. This loss in effectiveness is called tolerance. Evidence suggests that tolerance is not due to alterations in the brain’s responses to drugs. Animals exhibiting tolerance to morphine after repeated injections in a familiar environment show little or no tolerance when given the same doses and tested for pain sensitivity in new environments. Thus, there is almost certainly a learned aspect of tolerance. The cellular and molecular mechanisms underlying this loss of responsiveness are not clear. Physical dependence and addiction in a person using intravenous administration closely follow the dynamics of drug tolerance; increasing doses are required to produce the psychological effects, while tolerance protects the brain against the respiratory depressant actions of the drug. In the tolerant individual, intense adverse reactions can be precipitated by the administration of an opioid antagonist, thus revealing the dynamic internal equilibrium that previously appeared to neutralize the response of the brain to the opioids. The signs of the withdrawal response (e.g., anxiety, tremors, elevation of blood pressure, abdominal cramps, and hyperthemia) can be viewed as signs of an activated sympathetic nervous system and to some extent an extreme, but nonspecific, arousal response.

Dozens of compounds fall within this class of opioid analgesics, including hydrocodone, oxycodone, morphine, fentanyl, codeine, propoxyphene (recalled in 2010), hydromorphone (Dilaudid), and meperidine (Demerol), which is used less often because of its side effects. In addition to their effective pain-relieving properties, some of these medications are used to relieve severe diarrhea (eg, Lomotil, also known as diphenoxylate) or severe coughs (codeine).

What are the side effects of analgesics?

Your risk of experiencing side effects depends on the type of analgesic you take, and how long you take it.

Side effects of analgesics may include:

  • Constipation
  • Drowsiness
  • Dizziness
  • Upset stomach
  • Ringing in your ears
  • Skin itching or rash
  • Dry mouth

Analgesics Safety

Non-opioid analgesics have become increasingly emphasized in a variety of clinical settings as a preferred, safe and effective first-line therapy alternative to opioid medications for mild to moderate acute and chronic pain. Management of pain using opioid therapy requires a thorough assessment before initiation of treatment. When treating a person with chronic pain there may be physical, psychological, social, cultural, spiritual, and hereditary as well as behavioral factors that contribute to suffering and require attention and evaluation.

Opioids can cause unwanted or adverse effects. They usually cause drowsiness in the first 24 to 36 hours and patients should be advised that this will resolve. Constipation is a common side effect because opioids suppress receptors in the gut that guide peristalsis, leading to a slowdown in bowel motility.

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