Opioids: Both Blessing and Curse

Although the sensation of pain has evolved to help humans survive, it is obviously not a pleasant experience. A solution to this problem is seemingly quick and easy: opioid painkillers! While millions benefit from its pain-relief activity, opioids are also highly addictive, a nasty combination considering the serious side effects of an overdose. A crisis is emerging, stemming from the fact that prescription medications are now for sale on the internet, just a few clicks away. But how do opioid painkillers work, and what makes them so dangerously addictive?

A Brief History of Opioids

The typical painkillers you find at a pharmacy or drugstore are non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and aspirin. Steroidal painkillers provide the next level of pain relief, but these corticosteroids are unavailable over the counter and require a doctor’s prescription. However, the most powerful pain relievers remain a class of drugs known as opioids; they include morphine and its derivatives such as oxycodone and fentanyl.

Opioids get their name from the opium poppy plant that morphine is extracted from, although its synthetic derivatives also fall under the term. The analgesic effects of opium poppies have been exploited by humans for thousands of years, even though the active ingredient in opium, morphine, had not yet been identified. Today, the global opioid market value is an estimated USD 23 billion (2016), and it is still on the rise¹.

In the 19^th century, morphine was discovered as the compound responsible for opium’s analgesic and sedating properties. After extraction techniques were developed, it was found that different forms of morphine had superior pain-relieving properties. Additionally, virtually all these forms—heroin being a prime example—were found to be even more addictive than morphine².

Chemists around the world have since attempted to modify the structure of morphine in order to increase its potency while decreasing its addiction, resulting in a wide range of derivatives.

How Opioids Work

Opioids, as their name suggests, bind to opioid receptors. The three main classes of opioid receptors are μ (mu, pronounced ‘mew’), κ (kappa) and δ (delta), which together mediate the pain response. These g-protein-coupled receptors are mainly present in the nervous system as well as in the gastrointestinal tract.

Most opioids are able to bind with high affinity to μ-opioid receptors, activating them. This blocks the production of GABA, a chemical that inhibits signaling in the nervous system. Bocking GABA’s production, therefore, increases the amount of signaling. The result of this is the analgesic and sedative properties associated with opioid painkillers, while other side effects include depression of the respiratory system and increasing drug dependence (addiction)^4,5.

Because opioids work on different receptors, altering their structure leads to different binding profiles which result in different effects. As long as the main active group (the pharmacophore) remains, removal and replacement of the non-critical components of the molecule can lead to more potent, faster-acting, and less addictive variants; this is common practice to generate new leads in drug discovery.

How does our body get rid of opioids? They pass into the stomach and bloodstream before reaching our liver, where they undergo metabolism (chemical change) in two phases. In phase 1, cytochrome P450 (CYP450) enzymes oxidize the compound; different sub-families of CYP450 exist to metabolize a wide range of substances³.

Phase 2 metabolism involves glucuronidation by uridine diphosphate glucuronosyltransferase (UGT), which basically sticks a big functional group on the drug to make it more water-soluble. This is a common route for synthetic drugs that enter our bodies.

Metabolism in this manner aids in the excretion of the drug, as the product is more hydrophilic, increasing its solubility in water. This makes it easy for our body to remove the substance through urine.

Addiction and Substance Abuse

One of the major problems we face with opioid use is their high addiction potential; a staggering 1.8 million of the 35 million people with recorded opioid use in 2015 are classified as addicts^6,7. As mentioned, the activation of μ-opioid receptors by opioids is a double-edged sword. It reduces pain signaling but also rapidly increases tolerance to the drug, by altering the reward pathway in the brain.

Evidence for this can be seen in mice without the μ-opioid receptor gene; they display less addiction toward opioids but also react more sensitively to pain⁸.

Another problematic factor is the rapid buildup of tolerance with continued use, meaning that higher doses of the drug have to be administered for the same analgesic effects⁹. Since opioids also reduce respiratory function, increasing the dose can lead to insufficient oxygen in the blood; this is the primary cause of death by overdose.

The lethal dose of morphine for humans is around 120 mg, although death can occur with as little a dose as 60 mg. Individuals who exhibit drug dependence can consume 2000 – 3000 mg of morphine each session, hence putting them at a tremendous risk of overdose¹⁰. In 2017, more than 47 000 deaths were caused by opioid use in the US alone¹¹.

Ease of Access to Opioids

The factors related to opioid addiction and overdose are amplified when it becomes clear how easy it is to obtain them. Due to their label as the ‘gold standard’ for pain relief, it would be unethical to impose a total ban on their use. While a prescription is needed for its sale in most countries, doctors usually accede to requests for opioid-derived drugs if the patient claims to be in severe pain.

The emergence of ‘online pharmacies’ also plays a role in the ease of obtaining these drugs discreetly (and in many cases, cheaply). These websites do not require a prescription whatsoever, and dozens of different painkillers like fentanyl, oxycontin and morphine are readily available.

Furthermore, many of these ‘pharmacies’ also offer illicit drugs such as methamphetamines, cocaine and LSD, all contributors to drug-related public health crises. To make matters worse, drugs sold online are rarely regulated by governments. This means that many of these drugs are poorly manufactured or are even counterfeits, raising questions about their quality and safety.

As seen in the data above, there is a worrying upward-moving trend of opioid dependence and abuse. Part of this is due to the prevalence of internet access, making opioids cheaply available to more and more people. There is the main reason why opioid medicines are so tightly controlled, but at this point in time, we have no better alternatives. Until we find one, opioids remain our best form of pain relief.

Reference

1. Grand View Research. (2018). Opioids Market Size, Share & Trends Analysis Report By Product, By Application (Pain Relief, Anesthesia, Cough Suppression, Diarrhea Suppression, Deaddiction), By Region, And Segment Forecasts, 2018-2025.
2. Foundation for a Drug-Free World. The Truth about Painkillers: Painkillers: A short history.
3. Howard S. Smith. (2009). Opioid Metabolism. Mayo Clin Proc. July 2009; 84(7): 613-624.
4. Small Molecule Pathway Database. (2018). Fentanyl Action Pathway.
5. Ghelardini, C., Di Cesare Mannelli, L., & Bianchi, E. (2015). The pharmacological basis of opioids. Clinical cases in mineral and bone metabolism: the official journal of the Italian Society of Osteoporosis, Mineral Metabolism, and Skeletal Diseases, 12(3), 219-21.
6. United Nations Office on Drugs and Crime. (2017). World Drug Report 2017.
7. AddictionCenter. (2018). 10 most common addictions.
8. European College of Neuropsychopharmacology. (2007). How does the opioid system control pain, reward and addictive behavior?. ScienceDaily, 15 October 2007.
9. Dumas, E. O., & Pollack, G. M. (2008). Opioid tolerance development: a pharmacokinetic/pharmacodynamic perspective. The AAPS journal, 10(4), 537-51.
10. DrugBank. (2018). Morphine
11. Center for Disease Control and Prevention. (2018). Morbidity and Mortality Report (MMWR)