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A Big Pain – Opioids vs. Nsaids

by | Sep 15, 2023 | Drug Manufacturing


Since the 2016 bill signed by President Obama, the U.S. government has continued to take steps to address the opioid crisis. State-level initiatives have increased, including prescription drug monitoring and expanded treatment access. The Trump Administration enacted a 2018 package to improve treatment and curb synthetic opioids like fentanyl. In his 2022 State of the Union, President Biden mentioned investing in mental health and addiction services, although specific plans for the opioid crisis were not detailed.

Opioid pain medications manage the severe short-term or chronic pain of millions of Americans. While these medications mitigate needless suffering, joining forces are the government, corporations, and the medical community to battle opioid abuse and addiction.

What is the science behind Opioids? Let’s talk about how pain medications work, the different types on the market, and the approaches to developing less addictive versions of opioid drugs.


There are two main categories of pain medications, opioids and non-steroidal anti-inflammatory drugs (NSAIDs). Although these two categories of drugs work differently, they do share one thing in common: both are derivatives of natural products. The NSAID Aspirin (Bayer, Leverkusen, Germany) is a synthetic version of an extract from willow tree bark, and opioids are synthetic versions of opium and morphine, which come from poppy flowers.

Aspirin works by inhibiting an enzyme called cyclooxygenase 1 (COX-1). Once stopped, COX-1 can no longer produce signaling molecules called prostaglandins and thromboxanes. Prostaglandins and thromboxanes have a wide variety of functions, including mediating aspects of inflammation (fever and swelling) as well as promoting neuronal response to pain. Other NSAIDs, such as ibuprofen and naproxen, also work by inhibiting COX-1 or its sister enzyme, COX-2.

Opioid pain medications, such as certain widely known brands, work by binding to receptor proteins on the surface of cells in the central nervous system—think brain and spinal cord. While the central nervous system is tasked with relaying pain signals, opioids decrease the excitability of nerve cells delivering the message, resulting in pain relief—along with a feeling of euphoria in some users.


Short-term medical use of opioid painkillers rarely leads to addiction—when properly managed. Due to the euphoria-inducing effects of the drugs, long-term regular use or use in the absence of pain may lead to physical dependence and addiction. And because regular use increases drug tolerance, higher doses are required to achieve the same effect, leading abusers to consume pain pills in unsafe ways, such as crushing and snorting or injecting the pills. According to the Centers for Disease Control, 44 Americans die every day due to prescription painkiller overdose. At the same time, chronic pain is also a serious problem, affecting approximately 100 million U.S. adults, while millions of others suffer acute pain due to injury or surgery. The medical need for these drugs is very real despite the dark side.

The answer to developing less addictive drugs may be found in a drug that blocks pain without inducing euphoria. These new drugs will need a different mechanism of action than traditional opioid drugs, which bind to the mu receptors of cells inside the central nervous system. Cara Therapeutics (Shelton, CT) is developing drugs that bind to a different type of opioid receptor, the kappa opioid receptor. These receptors are present on sensory nerves outside of the central nervous system. In preclinical studies, CR845 (difelikefalin, brand name Korsuva) suggested that targeting these receptors could effectively reduce pain without driving addictive behaviors. FDA approved Korsuva in August 2021, after which it became the first and only therapy approved by the FDA to treat pruritus associated with chronic kidney disease.

Researchers at Indiana University are testing the pain management potential of a peptide—a small protein fragment—that binds to calcium channels in nerve cells. These channels control the flow of calcium through nerve cells and play a critical role in sending the pain signal to the brain. Preliminary studies suggest this new peptide is able to reduce the transmission of excitatory signals without completely blocking calcium transmission required for nerve function.


Overdosing can be fatal since respiratory failure occurs at high blood concentration levels of opioids. If an overdose is suspected, the individual should be treated as quickly as possible with naloxone—a “competitive antagonist” of the mu-opioid receptor. Simply put, a competitive antagonist binds the receptor without activating it. Since naloxone doesn’t activate the receptor, it doesn’t have any pain-relieving or euphoria-inducing qualities; rather, it prevents the opioid drugs from binding. It may also displace opioids that have already bound the mu receptor, aiding in the stoppage of an overdose.


The physical and psychological benefits of aerobic exercise are well known, and regularly active populations typically report feelings of calm and mild euphoria after moderate to intense activity. These feelings are linked to the production of endorphins— chemicals produced naturally by the body that bind to and activate the mu-opioid receptors. In fact, the word endorphin comes from the marriage of “endogenous morphine.”

Not everyone experiences the “runner’s high”—pretty much in the same way that not everyone experiences euphoric feelings from pain medications. These differences may help to explain why some people enjoy exercise and others don’t and why some people get addicted to opioids—while others can take them or leave them.


The opioid crisis is a complex issue that sits at the intersection of healthcare, policy, and individual well-being. While opioids are critical in pain management, their potential for abuse and addiction cannot be ignored. The medical community, governmental bodies, and pharmaceutical companies are working diligently to find safer alternatives for pain relief. Innovations like Cara Therapeutics’ Korsuva and ongoing research at Indiana University are promising steps toward a future where pain can be managed effectively without the risk of addiction. As we continue to explore the science behind opioids, it’s crucial to balance the immediate needs of patients with long-term public health goals. The path forward is fraught with challenges, but it’s a journey we must undertake collectively to mitigate the “big pain” that opioids have inflicted on society.


1. What are opioids and how do they work?

Opioids are a class of drugs that are used for treating moderate to severe pain. They work by binding to specific receptors in the central nervous system, reducing the excitability of nerve cells and thus alleviating pain.

2. How are opioids different from NSAIDs?

While both opioids and non-steroidal anti-inflammatory drugs (NSAIDs) are used for pain relief, they work through different mechanisms. NSAIDs like aspirin inhibit enzymes that produce inflammation-causing molecules, whereas opioids work by binding to receptors in the central nervous system.

3. What are the risks associated with opioid use?

Long-term use of opioids can lead to physical dependence and addiction. Additionally, they can cause respiratory failure in high doses, leading to fatal overdoses.

4. Are there any alternatives to traditional opioid medications?

Yes, there are ongoing efforts to develop less addictive pain medications. For example, Cara Therapeutics has developed Korsuva, which targets different receptors and has shown promise in reducing pain without addictive behaviors.

5. What is naloxone and how does it work?

Naloxone is a drug used to treat opioid overdoses. It acts as a “competitive antagonist” to the mu-opioid receptor, effectively blocking the binding of opioids and reversing the effects of an overdose.

6. What are endorphins?

Endorphins are chemicals produced naturally by the body that bind to and activate the mu-opioid receptors, providing natural pain relief and feelings of well-being.

7. Why do some people get addicted while others don’t?

The reasons for this are complex and can include genetic predisposition, environmental factors, and psychological conditions. Not everyone experiences the euphoric effects of opioids, which may explain why some people become addicted while others do not.

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Author: Emily Burke, PhD
Editor: Sarah Van Tiems, MS
Scientific Review: Tahir Hayat, MS


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