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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

Emily Burke, BiotechPrimer.com

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.

 

Juvenile Arthritis Awareness Month Underscores Efforts to Identify Causes and Develop Treatments

That’s right. Children get arthritis too. In fact, according to the Arthritis National Research Foundation (ANRF), nearly 300,000 children in the U.S. have been diagnosed with juvenile arthritis (JA) – one of the most common childhood diseases in the country.

Linda Barlow

Linda Barlow 

When Juvenile Rheumatoid Arthritis (JRA) first shows its symptoms in a child’s body, many parents write off swollen joints and fever as the flu, or think a sudden rash might have occurred from an allergic reaction. The symptoms might even recede slightly before showing up again, sometimes delaying diagnosis. 

Because a child’s immune system is not fully formed until about age 18, JRA can be especially virulent, compromising the body’s ability to fight normal diseases and leaving children open to complications that can adversely affect their eyes, bone growth and more.

Both the Arthritis Foundation and the ANRF are on the forefront of combatting this disease by supporting research into causes and treatments.

The ANRF’s Kelly Award is one example of how the organization dedicates part of its research effort toward treatment of JRA. The $75,000 grant is given annually to a researcher focused solely on JRA treatment and cures. For the past two years, the award went to Dr. Altan Ercan at Brigham & Women’s Hospital in Boston, whose work has the potential to provide novel targets for new therapies.

Another example is the Arthritis Foundation’s partnership with the Childhood Arthritis and Rheumatology Research Alliance (CARRA). Through the partnership, the Foundation is working to create a network of pediatric rheumatologists and a registry of children with the disease, allowing researchers to identify and analyze differences and similarities between patients and their responses to treatment. Ultimately, the registry will help researchers cultivate personalized medicine, the ultimate weapon in battling the disease. The CARRA Registry has been launched at 60 clinical research sites and has enrolled 8,000 patients.

The Arthritis Foundation has also committed to providing more than $1.1 million in funding this year to researchers investigating a wide range of topics, including: 

  • Exploring how environmental and genomic factors might play a role in triggering juvenile arthritis; 
  • Collecting data and evaluating the efficacy of standardized treatment plans; and 
  • Developing and testing a smart phone app to help children cope with pain.

According to the Arthritis Foundation, there is no single test to diagnose JA. A diagnosis is based on a complete medical history and careful medical examination. Evaluation by a specialist and laboratory studies, including blood and urine tests, are often required. Imaging studies including X-rays or MRIs may also be needed to check for signs of joint or organ involvement.

“When joint pain, swelling or stiffness occurs in one or more of your child’s joints for at least six weeks, it’s important not to assume these symptoms are temporary, and to get a proper diagnosis from a pediatric arthritis specialist,” says Arthritis Foundation Vice President of Public Health Policy and Advocacy, Dr. Patience White. “Early medical treatment of juvenile arthritis can prevent serious, permanent damage to your child’s joints and enable her to live an active, full childhood.”  

Management of JA depends on the specific form of the disease but can include:

  • Care by a pediatric rheumatologist.
  • Nonsteroidal anti-inflammatory drugs (NSAIDs) to control pain and swelling.
  • Corticosteroids such as prednisone to relieve inflammation, taken either orally or injected into inflamed joints.
  • Biologic Response Modifiers (BRMs), such as anti-TNF drugs to inhibit proteins called cytokines, which promote an inflammatory response. These are injected under the skin or given as an infusion into the vein.
  • Disease-modifying anti-rheumatic drugs such as methotrexate, often used in conjunction with NSAIDs to treat joint inflammation and reduce the risk of bone and cartilage damage.

One promising therapy in the fight against juvenile arthritis has been recently approved by the Food and Drug Administration – Actemra (tocilizumab) – from Roche. Used to treat polyarticular juvenile idiopathic arthritis (PJIA), the medicine can be used in children ages 2 and older. It is also approved for the treatment of active systemic juvenile idiopathic arthritis (SJIA).

How can organizations like the Arthritis Foundation and the ANRF increase awareness that arthritis happens to children, and build support to advance development of research and therapies?