On Thursday, April 5th, 2018, the Surgeon General of the United States, Dr. Jerome Adams, made a national advisory to the public: For patients currently taking high doses of opioids as prescribed for pain, individuals misusing prescription opioids knowing how to use naloxone and keeping it within reach can save a life (U.S. Department of Health & Human Services 2018). It was with this announcement that the drastic degree to which the opioid epidemic in the United States became alive in the mind of the public once more. Analgesics, or the broad term for pain-killer drugs, have long possessed relieving yet addictive qualities, and it is the hope of organic chemists in the pharmaceutical field to devise forms of these medications that avoid the potential for users extreme dependency on the chemicals, while simultaneously offering its originally intended medicinal effects.
Americas history with analgesics has been around since the mid-1800s, and distribution and addiction rates waxed and waned through to the early 1900s, where more regulations and restrictions on the sales and accessibility of the substance significantly reduced the amount of dependence the public was facing with the medicine; however, the 1980s sparked a renewed era of opioid use for chronic non-cancer pain, and doctors during that time began eagerly serving up opioids like their predecessors did during 1840 (Kolodny 2015). Health care professionals were being pushed to prescribe certain opiates introduced by pharmaceutical companies, and oftentimes the degree of a symptom being treated was not as highly regarded, despite the intensity of the medication. In actuality, there are various forms and strengths of analgesics available that are used to treat certain degrees of ailments. Popular items like aspirin and acetaminophen (Tylenol) both have anti-inflammatory properties and can help to reduce mild pain (Walker 2018). Despite the rather basic issues that these substances can address, overconsumption can lead to serious health concerns such as blood thinning, kidney and liver damage, and indigestion, to name a few (Walker 2018). Stronger analgesics are seen with opioid medications like morphine and oxycodone (OxyContin), which provides longer term pain relief for more severe symptoms (Reconnexion 2013). Unfortunately, history has shown that taking analgesics for its original medicinal intentions are often abandoned due to the addiction that can stem from its extended use.
The addictive qualities of opioids are explained through its mimicry to endorphins. Our brains natural pain reliever doesnt provide the degree of pleasure that its synthesized counterpart does, which is due in part to how the drug of focus can activate the mu opioid receptors responsible for eliciting powerful euphoric effects (Fudin 2018). Yet the withdrawal symptoms that come from insufficient drug dosages urge the user to consume more of the medication each time to reduce the pain theyre experiencing (Brookshire 2018). Fortunately, the issues that the chemistry of analgesics causes can be combated through the chemistry of receptor binding through opiate antagonists (Fudin 2018). Analgesics can also be referred to as agonists, as its function is to provide relief by binding to mu receptors to provide a feeling of euphoria; however, antagonists such as naloxone (Narcan) competes heavily against those particular receptors to suppress the binding of opioid drugs to those areas (Pubchem 2005). The fast-acting nature of this antidote is the reason it is so highly regarded by the public and other healthcare officials. But is it one of the medicines we need to use for a long-term solution to the analgesics conflict?
The effectiveness of antagonists has been credited by the surgeon general as being critical to ending the opioid epidemic (Jimison 2018). However, the rapid reaction that takes place with naloxone is both a saving grace and a potentially life-threatening circumstance, as the rate of the antidote helps to quickly unblock opioid receptors, but can also cause immediate withdrawal and, in some severe cases, heart arrhythmias (Sapko 2017). Another antagonist, naltrexone, is used by some alcoholics as well as opioid addicts for treating dependency (National Institute on Drug Abuse 2018). However, long term use of this medicine can induce symptoms such as bodily aches, elevated levels of liver and muscle enzymes, and negative behavioral changes (Sapko 2017). Despite the widespread availability of these medications in response to heightened addiction rates, there are some cases where antagonists themselves are not enough to reduce opioid-related mortality and may even increase opioid abuse (Jimison 2018). Unfortunately, medicine like naloxone is illustrated to mostly be used for situations in which an overdose episode is taking place. It is not a tool used for long term recovery in an individual, but it may give them another chance at life to eventually obtaining less harmful pain relievers and other routes of recovery that are currently being devised.
From the original natural opioid isolation to its synthetically derived compounds seen with heroin, oxycodone, and meperidine, biochemical research has had a lengthy track record of experimentation to reduce addiction rates, and now, there seems to be recent results of a promising series of studies that better illustrate the function of opioid receptors, or ORs. Two scientists in two different groups had similar goals: to synthesize drugs that had an improved pain-relieving effect but reduced the risk for tolerance in the user. James Zadina from Tulane University experimented with synthesizing compounds that attacked certain ORs for a more controlled medicinal effect, while former Stanford graduate student Aashish Manglik worked to better understand the crystal structure of the mu-OR. The efforts seen with Zadinas and Mangliks separate research ultimately reinforced each others findings, as it supports the idea we should be able to make agonists that separate the good from the bad effects (Crow 2017). Overall, the results of Mangliks study produced the PZM21 compound, which has had a reduced number of side-effects in comparison to its mainstream opioid counterparts through the improved binding potential (to mu-ORs), and very different chemical structures to existing opioids (Crow 2017).
Most elements in life are a double-edged sword, and the realm of pharmaceutical chemistry is no different. Americas landscape continues to face increasing addiction rates due to opioid medications, and it is a race against the clock to devise more effective forms of drugs in order to save lives amidst the tragically steep rates of over dosages. For now, this uphill battle is showing no sign of letting up, but the steady advancements and discoveries being made through analgesic studies signals the start of change for the health of our country and, eventually, the world.