The Science Behind Pain Relief

Pain, like love, is all-consuming. Whether it is the sharp pain of a twisted ankle or the constant discomfort of a backache, pain grabs your attention and makes everything else seem secondary. Unlike love, however, we do not have to endure pain without relief; we can turn to painkillers. This article explores the science behind painkillers, from over-the-counter medications to powerful treatments like opioids, shedding light on how they work and reduce our pain.

Why do we feel pain?

Pain is a highly disagreeable sensation, but it serves as an essential and extraordinarily complex alarm system to signal potential harm. Pain begins when specific neurons, called nociceptors, are activated and send electrical signals to the brain through the sensory nerves of the spinal cord. In the brain, these signals are processed and interpreted as the sensation of pain. Nociceptors respond to a variety of different stimuli such as mechanical injury, temperature extremes, or chemical substances released during inflammatory process (Dubin & Patapoutian, 2010).

While pain serves the critical purpose of alerting us to harm, it can sometimes become debilitating. This is where drug treatment steps in, offering tools to modulate the pain signal. Different classes of drugs address different stages of the pain signalling process, providing tailored relief for a variety of pain conditions:

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) work at the site of the injury, reducing the production of prostaglandins, which are chemicals that sensitize nociceptors.

• Opioids bind to opioid receptors to dampen the intensity of pain signals reaching the brain.

• Anesthetics act by blocking nerve conductance, thus interrupting the transmission of pain.

First line of defense: NSAIDs

When pain arises, Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) are often the first line of treatment. The primary mechanism of action for this class of drugs involves the inhibition of the PGG/H enzyme, widely known as COX. This inhibition prevents the conversion of arachidonic acid into prostaglandins. Preventing the body from forming prostaglandins has not only an analgesic effect, but also an anti-inflammatory effect. Stopping prostaglandin synthesis reduces the inflammatory response since these molecules play a crucial role in mediating this response, including vasodilation, increased vascular permeability, and recruitment of immune cells to the site of injury or infection. (Beale & Block, 2004).

It has been clearly shown that COX exists in mammals as two distinct isoforms: COX-1, which is constitutively expressed, and COX-2, which is inducible. COX-1 is produced under normal physiological conditions in most cells, with particularly high amounts in endothelial cells, platelets, and kidney tubular cells. On the other hand, COX-2 expression is induced by pro-inflammatory stimuli such as cytokines, bacterial lipopolysaccharide, growth factors, and tumour-promoting agents (Seibert et al., 1997).

Most NSAIDs inhibit both COX-1 and COX-2 enzymes, and based on their roles described earlier, the associated side effects become readily apparent. The synthesis of prostaglandins in the gastrointestinal tract and in the renal tubes plays a cytoprotective action for restoring the integrity of the stomach lining and maintaining renal functions. The inhibition of COX-1 by NSAIDs leads to the inhibition of the synthesis and release of bicarbonate and the mucus gel essential to protect gastric cells from erosion caused by gastric acid and other aggressive factors. Furthermore, maintenance of kidney function, especially in patients with congestive hearth failure, liver cirrhosis, or renal insufficiency, is reliant on the action of prostaglandins (Fiorucci et al., 2001).

Based on these observations, a vigorous concerted effort is being geared up to develop such newer drug substances that are selective for the COX-2 isoform. Structurally, the two isoforms COX-1 and COX-2 are very similar. However, despite their similarity, the active site for COX-2 is approximately 20% larger than the COX-1 binding site because of the replacement of isoleucine (Ile-523) in COX-1 with a smaller valine (Val-523) in COX-2. The exchange of an Ile for a less bulky Val causes a structural modification, that allows the access to an additional side pocket, which could lead to COX-2 selectivity (Zarghi & Arfaei, 2011).

Selective COX-2 inhibitors were developed by exploiting these structural differences between the two isoforms of the enzyme. Several selective drugs have been introduced to the market in the late 90s and in the early 2000s. Despite the promise, although they showed reduced gastrointestinal side effects, almost all COX-2 selective inhibitors have been withdrawn from the market due to cardiovascular risks (Beale & Block, 2004).

Figure 1: NSAIDs available at the pharmacy

Changing the game: the case of paracetamol

Paracetamol, also known as acetaminophen, is often singled out as a special pain relief because it lacks significant anti-inflammatory effects and primarily works by inhibiting a specific COX isoform. Its mechanism is still not completely understood, but it is generally assumed that it works in the central nervous system by blocking the brain-specific form of this enzyme. In 2002 a unique COX-1 variant was identify in the brain, which was designated as the COX-3 isozyme. It was hypothesized that this isozyme is - or can be - the target for acetaminophen. This hypothesis was supported by the evidence that the pain relief and antipyretic effects of paracetamol were accompanied by a dose-dependent reduction of brain prostaglandins, which is not observed with conventional NSAIDs. In addition, the peripheral levels of prostaglandins were reduced only by conventional NSAIDs but not by paracetamol. These evidences indicate that paracetamol provides pain relief and fever reduction without COX-2 inhibition action typical of conventional NSAIDs (Beale & Block, 2004).

Pain killers or pitfalls? Understanding opioids

Opioid receptors play a central role in pain management and the body’s response to pain. These receptors are specific proteins found on cell membranes throughout the central nervous system, including the brain, spinal cord, and gastrointestinal tract. When endogenous opioid peptides like endorphins, enkephalins, and dynorphins bind to these receptors, they inhibit the release of neurotransmitters such as substance P, which transmit pain signals. This action provides pain relief and affects other physiological processes such as mood, stress response, and respiratory function. Opioids work by targeting these receptors, offering significant pain relief but also bringing challenges such as potential side effects and the risk of addiction (Beale & Block, 2004).

There are three major subtypes of opioid receptors (Trescot et al., 2008):

• δ (delta) receptors, they are widely distributed throughout the brain, but their role is not yet completely understood. They may contribute to psychomimetic and dysphoric effects (Tok & Gowder, 2019);

• μ (mu) receptors: they are mainly located in the brainstem and medial thalamus; these are the most clinically targeted opioid receptors. Subtypes include Mu1, associated with analgesia, euphoria, and serenity, and Mu2, linked to respiratory depression, dependence, and sedation;

• κ (kappa) receptors: they are found primarily in the limbic system, brainstem, and spinal cord; they produce dysphoria.

  
  

All opioid receptors are part of the G-protein–coupled receptor family. When activated, a portion of the G protein diffuses within the membrane, inhibiting adenylate cyclase activity. This decreases cyclic adenosine monophosphate (cAMP) formation, leading to hyperpolarization of nerve cells and reduced release of pain neurotransmitters like glutamate and substance P (Trescot et al., 2008).

Morphine is the prototype ligand for the μ-receptor, isolated from opium in 1806 by German pharmacist Seturner. Although morphine was isolated in the 1800s, opium, from which it is derived, had been widely used in ancient times by the Romans, Egyptians, Arabs, and Chinese. The first mention of the opium poppy was found in Iraq on clay tablets inscribed in cuneiform script around 3000 BC. Opium is obtained from the unripe pod of the opium poppy (Papaver somniferum), where it is collected as latex. It contains over 40 different alkaloids, with morphine being the most abundant among them (Beale & Block, 2004).

From a chemical perspective, morphine is a very complex molecule, featuring five rings, five chiral centers, and sixteen optical isomers. Given its intricate structure, it is not surprising that although morphine’s total synthesis has been achieved through various chemical processes, it is still primarily produced from the poppy latex (Beale & Block, 2004).

Morphine is the prototype and reference for the entire class of opioid drugs. It serves as the benchmark against which other opioids are measured. Many opioids currently on the market are natural derivatives with chemical structures similar to morphine, such as codeine and oxycodone. However, extensive medicinal chemistry research has identified key molecular portions of morphine, leading to the development of non-natural opioids with similar or even improved effects. These synthetic opioids have simpler chemical structures than morphine, making them more easily producible. Examples include fentanyl, which is more potent than morphine, and methadone, which offers a longer duration of action for pain management and addiction treatment (Beale & Block, 2004).

The use of opioids, in general, is constrained by their side effects and the risk of addiction. While they are effective in providing pain relief, opioids can cause a variety of adverse effects including respiratory depression, nausea, constipation, dizziness, and sedation. Long-term use often leads to tolerance, where higher doses are required to maintain pain relief, and physical dependence, which can trigger withdrawal symptoms if the drug is suddenly discontinued. Additionally, opioids carry a significant risk of addiction, particularly with potent formulations. This risk of misuse and abuse highlights the need for careful patient selection, dosing, and monitoring to balance the therapeutic benefits with the potential hazards of opioid therapy (Beale & Block, 2004).

Figure 2: lethal dose of fentanyl (2 mg)

The dark side of heroin

Heroin was first commercialized in 1898 by Bayer (Germany) as an over-the-counter drug. The laboratory researchers believed that heroin would be an effective analgesic with no addictive properties. Unfortunately, this was not the case. Heroin can pass through the blood-brain barrier quicker than morphine and lead to the euphoric “rush” that becomes so addictive for individuals with addiction, especially after IV injection. Once heroin is in the brain, it is quickly metabolized to 3-acetylmorphine, which has low to zero activity at the μ-receptor and 6-acetylmorphine, which is 2 to 3 times more potent at the μ-receptor than morphine (Casy & Parfitt, 1986).

Today, some countries have adopted heroin-assisted treatment (HAT) programs as a medical approach to address severe opioid use disorders. In nations such as Switzerland, Germany, the Netherlands, United Kingdom, Denmark, and Canada, heroin is prescribed under strict medical supervision to individuals who have not responded to other treatments. In the United Kingdom, beyond addiction treatment, heroin is also utilized in controlled doses for palliative care, offering relief from severe pain in terminal illnesses (Drug Policy Facts, n.d.).

Loperamide: an opioid beyond pain relief

Loperamide is a synthetic opioid  with a unique role in gastrointestinal care rather than pain management. Unlike other opioids, its primary use is to treat diarrhea, acting on gut wall release. This decreases peristalsis and fluid secretion, thus increasing the gastrointestinal transit time and reducing the volume of fecal matter. Loperamide is sufficiently lipophilic to cross the blood-brain barrier, yet it displays no CNS-opioid effects. The reason for this is that it is actively pumped out of the brain via the P-glycoprotein pump (Beale & Block, 2004).

Figure 3: Bayer heroin bottle

Conclusions

Pain is a complex and essential alarm system. It begins when nociceptors, which are specific sensory neurons, are activated and transmit signals to the brain through the spinal cord. These signals are interpreted by the brain as pain. While it can be debilitating, especially when chronic, there are numerous medical interventions available to manage and mitigate pain. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), such as aspirin and ibuprofen, are commonly used for their analgesic and anti-inflammatory effects. While effective, NSAIDs can cause gastrointestinal side effects due to their inhibition of COX-1, which is involved in maintaining the protective lining of the stomach. They also pose risks to renal function, especially in individuals with pre-existing kidney conditions. Opioids, such as morphine and fentanyl, work by binding to opioid receptors. This action inhibits the release of pain-transmitting neurotransmitters like substance P, providing significant pain relief. However, they can cause a range of side effects, including respiratory depression, constipation, sedation, and dizziness. Long-term use can lead to tolerance, dependence, and addiction, making monitoring critical in opioid therapy.

Bibliographical References

Beale, J. M., Jr., & Block, J. H. (Eds.). (2004). Wilson and Gisvold’s textbook of organic medicinal and pharmaceutical chemistry (12th ed.). Lippincott Williams & Wilkins.

Casy, A. F., & Parfitt, R. T. (1986). Opioid analgesics: Chemistry and receptors. Plenum Press.

Drug Policy Facts. (2023, July 22). Heroin-assisted treatment (HAT). https://www.drugpolicyfacts.org/chapter/hat

Dubin, A. E., & Patapoutian, A. (2010). Nociceptors: The sensors of the pain pathway. Journal of Clinical Investigation, 120(11), 3760–3772.

Fiorucci, S., Meli, R., & Cirino, G. (2001). Dual inhibitors of cyclooxygenase and 5-lipoxygenase: A new avenue in anti-inflammatory therapy? Biochemical Pharmacology, 62(11), 1433-1438.

Seibert, K., Zhang, Y., Leahy, K., Hauser, S., Masferrer, J., & Isakson, P. (1997). Distribution of COX-1 and COX-2 in normal and inflamed tissues. Advances in Experimental Medicine and Biology, 400A, 167–170.

Tok, T. T., & Gowder, S. J. T. (2019). Structural and Pharmacological Properties of Alkaloids with Special Reference to Thebaine Type Alkaloids. Biomed Journal of Science & Technology Research, 17(3).

Trescot, A. M., Datta, S., Lee, M., & Hansen, H. (2008). Opioid pharmacology. Pain Physician, 11 (Opioid Special Issue), S133–S153.

Zarghi, A., & Arfaei, S. (2011). Selective COX-2 inhibitors: A review of their structure-activity relationships. Iranian Journal of Pharmaceutical Research, 10(4), 655–683.

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