A Brief History of Painkillers (And Why They Work)

It’s almost impossible to imagine a world without pain relief. We depend on these drugs to an unspeakable degree, yet few of us know what’s available or how they even work. Here’s a quick primer on painkillers and why they’re so good at easing the pain.

We deal with pain on an almost daily basis. It’s nature’s not-so-subtle way of telling us that we should stop doing what we’re doing or that we’ve injured ourselves. In the future, owing to advanced biotechnological engineering, we may choose to replace this clunky method with something less unpleasant. But for now, we have to deal with it.

A Brief History of Painkillers (And Why They Work)

Above: Arnold Schwarzenegger and Sylvester Stallone posing together in hospital beds after receiving treatment for injuries sustained from movie stunts. Taken in 2012 (Reuters/Arnold Schwarzenegger/Whosay.com)

Indeed, up to 40% of people experience undue pain on a daily basis. Things like headaches, menstrual cramps, back pain, arthritis, and throbbing injuries. Pain can also come from such things as physical trauma, degenerative disorders, and uncontrolled pain following surgery. Nearly 50 million Americans suffer from chronic pain and it costs the U.S. $100 billion each year. Pain is undertreated in nearly half of patients with cancer.

Thankfully, there’s pain relief, and a wide variety of drugs to choose from. But it can often get confusing. To help, we’ve put together this primer on pain relief to help you know what’s out there.

But first, a little bit of history.

A Painfully Brief History of Pain Medication

Humans have been practising various forms of pain management for thousands of years. Stone Age peoples, believing that pain and disease were punishments handed down by the gods, tried various techniques to banish away the pain, like presenting religious offerings and sacrificing animals. They also used rattles, gongs, and other noise-making devices to frighten malevolent spirits out of a person’s body. Some Native American cultures sucked on pain pipes held against a person’s skin to extract the pain or illness, while South Americans practiced trepanation — the cutting of holes in the head to alleviate pain.

In Ancient Egypt, electric eels were taken from the Nile and laid on the wounds of patients — not too ridiculous when you consider that a similar technique, called Transcutaneous electrical nerve stimulation, or TENS, is sometimes used today for lower back pain and arthritis aches. The Ancient Greeks, on the advice of Hippocrates, used willow bark and the chewing of willow leaves to help women during childbirth — and they weren’t too far off the mark. Willows contain a form of salicylic acid, the active ingredient of aspirin.

By the Middle Ages, a variety of herbs were used, including theriac, a concoction prepared in a honey base with about 64 different compounds in it.

Opiates have also been used for thousands of years, an analgesic originally derived from the opium poppy. Morphine, the active substance, was named after Morpheus, the Greek god of dreams. Opiates represented an entirely new class of pain relief. They was extremely powerful, but also very addictive.

During the 16th Century, early chemists created laudanum, an opium prepared in an alcoholic solution. But by the 19th century morphine was extracted in its pure form. And that’s when it really took off. By the 1830s, drug dependency reached disturbing proportions, leading to the mobilization of British warships along the Chinese coast to suppress opium traffic — the so-called “First Opium War.”

Later that century it was used during the American Civil War. Again, effective, but highly addictive.

There were a number of attempts to replicate the effectiveness of morphine, but with mixed results. The Antikamnia Chemical Company developed Antifebrin, a catastrophic drug that used acetanilide as its active ingredient, one that had the regrettable effect of stopping the flow of oxygen to the blood. Interestingly, Antifebrin contains paracetamol, or acetaminophen, which is now one of the world’s most popular pain relievers.

As noted, aspirin goes back for millennia, but it wasn’t properly formulated until 1895 by Frederick Bayer and Felix Hoffman.

Codeine, a naturally occurring methylated morphine, was first isolated in France in 1830 by Jean-Pierre Robiquet to replace raw opium for medical purposes. It was primarily used as a cough remedy, but it’s still in use today in such products as Tylenol 3. Chemists also developed heroin in an effort to create something less addictive than morphine — but they ended up developing something with twice the addictive qualities.

The U.S. banned opium in 1905, and the following year the Pure Food and Drug Act was passed, requiring contents labeling on all meds.

In 1937, German scientists Max Bockmuhl and Gustav Ehrhart synthesized methadone while working for the IG Farben Company — the same firm that produced the toxic Zyklon B gas used at Nazi extermination camps. The researchers were hoping to devise pain medication that could be easily administered during surgery. They ended up creating something far more addictive than even heroin.

By the late 20th century, a new breed of painkillers hit the market — synthetic opiates which mimic the body’s natural painkillers. Common names including Vicodin (1984), OxyContin (1995), and Percocet (1999).

Painkiller Taxonomy

Today, there are many different types of pain relievers (including specialized ones that can only be delivered medically). But for the purposes of this Explainer we’ll limit the discussion to the most pertinent:

  • Nonsteroidal anti-inflammatory drugs (NSAIDs)
  • Acetaminophen
  • Opioids
  • Muscle relaxants
  • Antidepressants
  • Anticonvulsants
  • Topical agents

How They Work

Nonsteroidal anti-inflammatory drugs (NSAIDs)

These are chemicals that act on bodily processes that cause inflammation, pain, and fever. Examples include aspirin (the most widely used drug in the world), ibuprofen, naproxen, and indomethacin. They represent a diverse class of drugs and are among the most commonly used pain relievers worldwide. It’s estimated that NSAIDs are used by 30 million people every day.

They’re particularly prized for the way they help alleviate the discomfort caused by osteoarthritis and rheumatoid arthritis, though they’re often associated with gastrointestinal and cardiovascular risks.

When we experience pain, it’s the result our nociceptors firing away. When our cells are damaged, from things like blunt trauma or a sharp pin-prick, they produce tuning chemicals that lower our nociceptors’ threshold to the point where even simple contact with the area causes pain, which we call soreness. We hate this, so we take NSAIDs.

A Brief History of Painkillers (And Why They Work)

These pain relievers, like ibuprofen and aspirin, block the production of a very special class of tuning chemicals called prostaglandins. Our cells release arachidonic acid when they’re damaged; the enzymes COX-1 and COX-2 convert the arachidonic acid into prostaglandin H2, which is then turned into a series of other chemicals which do such things as raise our body temperature, cause inflammation, and lower our pain threshold. Credit: rsc.org

NSAIDs interfere with this process, raising our pain threshold. Aspirin performs this task by blocking the way arachidonic acid fits within the COX-1 and COX-2 enzymes, permanently deactivating them. Ibuprofen does it in a similar way, but temporarily. All these drugs work in an untargeted way, doing their business throughout the body and impacting on all its areas.

This awesome TED-Ed video explains it well:

Acetaminophen

Also called paracetamol, these are mild analgesics that do little to treat inflammation (which is why they’re not classified as NSAIDs), but they increase the body’s pain threshold. Brand names include Tylenol, Crocin, Tempra, Datril, and Panadol. It’s commonly used to treat headaches and other aches and pains. Paracetamol a major ingredient in many cold and flu remedies.

The U.S. Food and Drug Administration warns that taking 25% above the daily maximum dose can cause liver damage when taken over several days. And indeed, during the last decade more than 1,500 Americans died after taking too much of it.

Acetaminophen is derived from coal tar and is the active metabolite of phenacetin. Strangely, the precise way that it confers pain relief is not entirely known. It likely incompletely inhibits the COX-1 and COX-2 enzymes. It may also inhibit the COX-3 enzyme in the brain.

Acetaminophen can also be used in conjunction with opiates, providing a very powerful means of pain management.

Narcotic analgesics

Also known as opioids, these chemicals modify pain messages in the brain. Examples include tramadol, morphine, methadone, fentanyl, meperidine, and codeine (considered a weak opioid). As already discussed, opioids have a long and notorious history. But they work remarkably well; opioids decrease the perception of pain, decreasing reaction to pain, as well as increasing pain tolerance. But the side effects, along with dependency, include sedation, respiratory depression, constipation, and a strong sense of euphoria.

Opioids work by interfering with the pain signalling at several distinct anatomical areas:

A Brief History of Painkillers (And Why They Work)

Anatomic targets for analgesics. 1. Nociceptors and surrounding tissue. 2. A-delta and C fibers. 3. Dorsal root ganglions. 4. Dorsal horn synapses. 5. Ascending pathways. 6. Intracranial neurons and glial cells. 7. Descending pathways. Via Slater et al.

They bind to opioid receptors primarily in the central and peripheral nervous system and the gastrointestinal tract. And interestingly, cannabis augments the pain relieving effects of opioids — but they are not classified as opiates (marijuana would probably be best classified as an antidepressant analgesic, or even a category unto itself).

Muscle relaxants

These drugs, sometimes called sedatives, reduce the pain caused by tense muscle groups, typically through calming action in the central nervous system, namely the spinal cord, brainstem, and cerebrum. Brand names include Soma, Flexeril, Valium, Skelaxin, and Robaxin. They’re particularly effective for lower back pain. Muscle relaxants are also used in treating spasticity-related muscle pain in patients with stroke, multiple sclerosis, or after spinal cord injury.

The most common muscle relaxant is cyclobenzaprine, and it works by depressing the effects of serotonergic neurons. Methocarbamol works by suppressing spinal reflexes, but without any direct effect of skeletal muscle.

Anti-anxiety drugs and antidepressants

Pain can also be treated by reducing anxiety, relaxing muscles, and by helping people cope with discomfort. Some antidepressants, like tricyclics (including amitriptyline), can reduce pain transmission through the spinal cord. An effective SSRIs for pain relief is duloxetine (Cymbalta). More on this class of analgesics here.

Anticonvulsants

These drugs are typically used to treat neuropathic pain, a form of chronic pain caused by injury or disease of the peripheral or central nervous system. They work by stabilizing nerve cells.

Carbamazepine, the first anticonvulsant studied in clinical trials, alleviates pain by decreasing conductance in specific neurological channels. Results from clinical trials have been positive in the treatment of trigeminal neuralgia, painful diabetic neuropathy and postherpetic neuralgia. Other anticonvulsants include gabapentin (Neurontin) and pregabalin (Lyrica).

Topical analgesics

Sometimes topical agents, like a cream or gels, can be used to treat soreness. Some soothing creams include capsaicin (yes, the same substance that gives hot chilis their heat), diclofenac, and lidocaine. Corticosteroids are a class of pain relievers exert powerful anti-inflammatory effects and are typically used to alleviate the pain derived from physical injuries.

Others

Other pain relievers not discussed include nerve block injections (when an anesthetic is injected into the affect nerve to relieve pain), epidural steroid injections (by injecting steroids into the spine, typically during childbirth), and trigger point injections (the injection of local anesthetic into specific tender areas).

As a final note, it’s important to mention that prescription painkillers are now the leading cause of accidental deaths in the United States. If you’re going to use pain relief, please do so wisely and in consultation with your family doctor. And if you’re addicted, seek help.

Additional reporting by Joseph Bennington-Castro.
[ Other sources: A Brief History of Pain | WebMD | Top photo: Arman Zhenikeyev/Shutterstock ]