A Big Pain
Editor’s Note: This article in our pain management series originally appeared in Biotech Primer Weekly. For more of the science behind the headlines, please subscribe.
The Science Behind Opiods
The opioid addiction epidemic gained attention at the highest levels of U.S. policy circles this past year, as presidential candidates that disagreed on nearly everything else vowed to make fighting the problem a priority if elected. In July, the U.S. Senate overwhelmingly approved a bill to strengthen prevention, treatment, and recovery efforts. And no wonder – according to the Center for Disease Control, opioid overdose deaths are at an all-time high – a stark reality that 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.
We 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.
Opiods 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 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 Oxycontin and Percocet, work by binding to mu receptor proteins on the surface of cells in the central nervous system (CNS) —think brain and spinal cord. While the CNS 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 CNS. Drugs under development include those that bind to a different type of opioid receptor, the kappa opioid receptor. These receptors are present on sensory nerves outside of the CNS.
Preclinical studies suggest that targeting these receptors could be effective at reducing pain without driving addictive behaviors. A lead candidate, CR845, is currently in Phase 3 clinical testing for post-operative pain and pruritus (severe itching), and in Phase 2 clinical testing for chronic pain. Also under development are compounds that selectively activate cannabinoid (CB) receptors outside of the CNS. CB receptors inside the CNS are linked to the psychoactive qualities of marijuana; those outside the brain are found on white blood cells and have been shown to be involved in decreasing pain and inflammation. A lead CB receptor activator, CR701, is in preclinical development.
Also under development are small molecule inhibitors of ion channels – proteins on the surface of nerve cells that help to transmit pain signals by allowing positively charged calcium ions to enter the nerve. This plays a critical role in sending the pain signal to the brain, yet because it works on nerves outside of the brain, it has less of a potential for addiction. Phase 1 clinical studies are currently underway of HX-100 for the treatment of painful diabetic neuropathy.
Another development is a derivative of capsaicin, a naturally-occurring compound found in chili peppers. Capsaicin has pain relieving properties and has been used as a natural remedy. The lead candidate, CNTX-4975, is a highly potent, synthetic form of capsaicin designed to be administered via injection into the site of pain. CNTX-4975 targets the capsaicin receptor, an ion channel protein on the surface of nerve cells. When CNTX-4975 binds the capsaicin receptor, the influx of calcium ions results in desensitization of the nerves, making them unresponsive to other pain signals. This effect can last for months, and only affects nerves near the site of injection. CNTX-4975 is currently in Phase 2b clinical studies for knee osteoarthritis, and Phase 2 clinical studies for Morton’s neuroma, a sharp pain in the foot and toe caused from a thickening of the tissue around one of the nerves leading to the toes.
Earlier this year, researchers at Tulane University published a paper that shows great promise for the development of effective yet non-addictive pain medications. They have developed a compound that is derived from the endogenous opioid endomorphin. Endogenous opioids are chemicals produced naturally by the body that bind to and activate the mu opioid receptors, resulting in pain relief and mild euphoria without the detrimental side effects associated with opioid drugs such depressed respiration, motor impairment, and addiction. Scientist have tried before to develop safer pain medications based on endogenous opioids, but have not been successful, due to the instability of these molecules. The Tulane team created a derivative of endomorphin that is stable and binds to the mu receptor in such a way that pain relief occurs, but not the negative side effects listed above. Clinical testing is expected to begin by the end of 2017.
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.
Cocktail Fodder: Runner’s High
Some folks love to run; others avoid it at all costs. This might be explained by inherent differences in sensitivity to the natural opioids called endorphins that are released during exercise. Not everyone experiences the “runner’s high” — feelings of calm and mild euphoria – just like 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.