How Do Painkillers Know Where the Pain Is?

Dr. Ximena Sanchez-Samper

Ximena Sanchez-Samper, MD is a Board- Certified Addiction Psychiatrist who obtained her degree as a psychiatrist at the Mayo Clinic in Rochester, MN and completed her Addictions Fellowship through the combined Massachusetts General Hospital, McLean Hospital / Brigham and Women’s Hospital Addictions Fellowship program in 2004.

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How Do Painkillers Pinpoint Pain?

From mild over-the-counter analgesics to the powerful drugs administered during surgical procedures, all painkillers have a few things in common. They work by blocking the neural pathways that cause pain, but have you ever wondered why they only seem to work on the affected area? Why doesn’t your entire body go numb? The answers lie in understanding exactly what painkillers do within the body and how they work. 

What Causes Pain?

In order to understand how painkillers work, it’s crucial to understand how the body processes the feeling of pain. Pain can be caused by a physical injury or damage to the tissues of the body, disease, or inflammation. Pain is a way that the body alerts the brain that something is not right and that something needs to be done about it. The experience of pain begins with a signal from a set of specialized nerve cells throughout the body. These specialized nerve cells, called nociceptors, receive impulses from the damaged area and transmit them to specialized pain receptors in the brain. 

The impulses travel along pathways that are devoted to pain impulses. These pain pathways throughout the body all converge in the brain stem. From there, the signals are transmitted to certain areas of the brain. One area of the brain that receives these signals is the thalamus. 

You could think of the thalamus as the central switching station of a train yard. It routes the signals to other parts of the brain, including those in the cortex on the outer layer of the brain. This generates the experience of pain. Pain is useful and can help you know when there is danger, such as feeling the heat from a fire and knowing to move away. 

Pain involves three components that must be processed. The first is the ability of the brain to localize where the source of the pain is located in the body. The second is producing the emotion that the pain is unpleasant. The third component is developing a plan to avoid the pain in the future. This is why you do not move your foot away when you cut yourself on the hand. Instead, your brain knows which body part needs to respond, which is rather a quite complex process in itself. 

The emotional aspect of pain and the judgment that it is an unpleasant experience occur in the same brain system and pathway responsible for the emotions of anger, anxiety, and fear. Several neurotransmitters interact to produce the sensation of pain in the body, and others block the signal and reduce the pain. Here are the major players. 


Glutamate is a neurotransmitter that is responsible for making the pain persist and plays a role in chronic pain. Developing drugs that work by blocking glutamate receptors has been receiving considerable attention because of its ability to reduce chronic pain. 

Gamma-aminobutyric Acid (GABA)

GABA plays a role in blocking the activity of neurons. It reduces pain by preventing spinal cord signals from transmitting the signal to the brain. This dampens the pain and works in a similar way to analgesics. One of the difficulties in developing analgesics that work like GABA is that this chemical is so common in the body systems that any drug that suppresses the same system would also impair autonomic body functions and the central nervous system, such as those that control your heart and lungs. 

Norepinephrine and Serotonin

Norepinephrine and serotonin work by blocking the signal at the site of the injury or source of the pain. Drugs that block receptors for these neurotransmitters have been known to help relieve chronic pain and migraines. This is one of the reasons that some antidepressants have the side effect of helping to reduce chronic pain. 


Opioids are involved in both the sensation of pain and the reward centers of the brain. One of the interesting aspects of the brain is that it has a protective mechanism that prevents further harm by causing pain and an appropriate response, but it also has a natural dampening system that can reduce the power of the signal. It does this by releasing natural opioids that block the signal and reduce the intensity of it as it travels to the brain. Opioids, such as morphine, mimic the effects of our body’s natural opioids, but they are extremely potent and used for severe pain. 

What Types of Painkillers Are Available?

Over-the-counter pain medications are classed as analgesics, aspirin, and anti-inflammatory drugs. Narcotics are a class of prescription painkillers. Even though they work similarly, they do so using different methods of action

Nonopioid Analgesics

The most common nonopioid analgesic is acetaminophen, which is also known as paracetamol. It is used for mild to severe pain and can be used to boost the painkilling effect of opioids. It can also reduce fever. However, analgesics are not known to be effective in pain caused by neuropathy. 

Acetaminophen has been around for about 150 years, and how it works is still not understood completely. It is believed that it works by reducing the total amount of pain-causing enzyme production, which means the pain signal cannot be transmitted. Acetaminophen works by suppressing the entire central nervous system and does not specifically target the site of the pain like analgesics do. Acetaminophen is in a drug class all its own and does not work in the same way as nonsteroidal anti-inflammatories. 

Nonsteroidal Anti-inflammatory Drugs

Nonsteroidal anti-inflammatories (NSAIDs) are used for mild to moderate pain that is a result of inflammation. They can also temporarily reduce a fever. They also do not work on neuropathic pain. Ibuprofen, naproxen, and aspirin are some of the more common over-the-counter NSAIDs. 

These drugs work by reducing pain at the injury site instead of suppressing the entire pain transmission system. When we are injured, our body releases cytokines at the injury site, such as where a bone is broken or the skin is scraped. Cytokines are a group of proteins that are a part of the immune system and nervous system. Their job is to help respond to an injury and fight off disease. They trigger pain by causing inflammation, but they can also do this when no injury is present. After an injury, cytokine levels rise. NSAIDs work by blocking cytokine receptors and preventing the transmission of pain from the injury site. 


Analgesics work by reducing inflammation by blocking cytokine release or by changing the way the brain processes pain. They are used for both acute and chronic pain. They only work at the site of the injury or source of the pain by seeking out cytokine receptors. Local analgesics applied to the skin work by blocking certain calcium channels necessary for pain impulses. 

Opiates and Opioids

Opioids and opiates both work by activating the opioid receptors in the central and peripheral nervous system. By blocking these receptors, the pain impulses cannot be transmitted. They also tend to increase feelings of pleasure, which compounds the lower perception of pain. The difference between opiates and opioids is where they’re produced; opiates occur naturally, and opioids are synthetic. Some of the more common opioids include: 

  • Fentanyl
  • Oxymorphone
  • Hydrocodone (Vicodin) 
  • Oxycodone (Oxycontin, Percocet)

Common opiates include: 

  • Codeine
  • Morphine
  • Heroin
  • Opium

How Do Painkillers Know Where the Pain Is?

When you get back to the initial question, the truth is that only two types of painkillers–anti-inflammatories and analgesics–actually “know” where the site of the pain is and work to relieve it at the site. They do this by seeking out the cytokines that our bodies release in response to an injury. 

The other types of painkillers do not actually “know” where the pain is; they work by reducing the number and strength of pain signals produced by the body. Fewer pain signals reach the brain, which reduces the perception of pain overall. The perception is that pain is reduced at the site because the entire pain transmission system is suppressed. 

Some antidepressants and antiepileptics are used to control chronic pain. Antidepressants work to control pain by manipulating serotonin and norepinephrine levels. Antiepileptic medications work by controlling GABA levels. These medications do not “know” where the pain is located but work by modulating the associated chemicals in the entire brain and body. 

Side Effects and Addiction Associated With Painkillers

The mechanisms that create the sensation of pain are complex, and methods that are used to control pain work using different methods. One of the challenges with pain management is that some of the compounds used can be addictive. One of the most addictive is opioids because they reduce the pain, and they also activate the pleasure centers of the brain. This can make someone who takes them crave them even when the source of the pain is healed and can cause addiction. 

Are You Addicted to Painkillers?

Regardless of how the addiction began, if you or a loved one is dependent on opioids or any other type of pain medication, it is time to break the cycle. When used over a long period, these drugs cause changes in the brain, and you could go into withdrawal if you just decide to stop taking them without support. If you notice any of these symptoms in a family member or friend, it might be time to get help: 

  • Self-isolation
  • Reduced hygiene or negative changes in appearance
  • New financial or legal struggles
  • Weight loss, frequent illness, or obvious drowsiness
  • Reduced interest in work, hobbies, or family events

If you notice any of these signs, it is important to contact Charles River Recovery. Our team can help you break the addiction and return to your best life. 

Treatment for Painkiller Addiction

Between 3% and 19% of people who are prescribed legally to prescription painkillers become addicted to them. However, help is available at Charles River Recovery. 

A client who enters treatment will start with a medical detox. This is where they are weaned off of painkillers using medications that can ease the uncomfortable and sometimes dangerous side effects of painkiller withdrawal. 

After detoxification, clients will transition to either inpatient or outpatient treatment. Inpatient treatment is best suited for those with a long-standing addiction or for someone who is taking a very high dose. This person may no longer have a stable home or social environment or may have experienced legal consequences as a result of their addiction. 

Outpatient treatment allows clients to live at home while receiving therapy and treatment. This plan is perfect for someone who has a stable support system at home or who has work, school, or family obligations that prevent them from attending treatment full-time. 

We can help ease the withdrawal period and work toward building the foundation for long-term recovery from painkiller addiction. We can help with prescription drug dependence and non-prescribed opioid addiction. Our team is experienced, caring, and dedicated to helping you succeed in breaking your painkiller addiction for good.