The Science Behind Opioids

President Obama’s recent plan to fight opioids highlights the dark side of a class of treatments serving a vital need. 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 medical community to battle against opioid abuse and addiction.

Here at WEEKLY, we always wonder: what is the science behind the headlines? So, 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.

Opioids vs. NSAIDs

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 cyclooxyrgenase 1 (COX-1). Once stopped, COX-1 is no longer able to 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 Purdue Pharma’s (Stamford, CT) Oxycontin and Endo Pharmaceuticals’ (Malvern, PA) Percocet, 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.

Lessening The Pain

Short term medical used of opioid pain killers 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. Preclinical studies suggest that targeting these receptors could be effective at reducing pain without driving addictive behaviors.

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.

An Antidote To An Overdose

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.

Endorphins, The Natural Opioids

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.

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