Introduction
For thousands of years, opioids have been used in the treatment and relief of severe or chronic pain making them one of the longest used class of medications (Lanier & Kharasch, 2009, page, 572). Opioids are unique in the way that they can make a strong limitless impact on pain without impairing sensations like temperature, touch, or position (Pasternak, 2014, page, 1655). Although the pharmacokinetic parameters of opioids have been known for some time (such as the half-life, distribution and overall effects within the body), the mechanism of how this drug class works has only been discovered in the last few decades (Trescot et al., 2008, page, S134).
In the early 1970s, scientists have found that opioids derive from precursor hormones that are cleaved to activate three classic opioid receptors (Pasternak, 2014, page, 1658). These ligands work on three main classes of opioid receptors named the mu, delta, and kappa receptors (Pathan & Williams, 2012, page, 11). Ligands work as agonist, partial agonist or mixed agonist-antagonist, or antagonist depending on the drug and receptor it acts upon (Pasternak, 2014, page, 1656). Opioid are diverse in their onset of action and duration in the body, depending on the opioid itself as well as the route of administration (Lanier & Kharasch, 2009, page, 572). Some of the more common routes of administration include intravenous infusions, subcutaneous, patient controlled dispension, transdermal patches, trans mucosal oral dosage forms, nasal sprays, and aerosols (Lanier & Kharasch, 2009, page, 572-573).
Short term use of opioids resolves instantaneous pain, however longer use can cause negative effects such as abuse, addiction and even death. That is not to say these events occur in pain management for cancer patients who receive controlled low doses of opioids for treatment, but shows that opioids are powerful medications that have the potential to be abused and misused.
MECHANISM OF ACTION
Opioids act upon 3 main receptors: mu opioid receptors (MOR), delta opioid receptor (DOR), and kappa opioid receptor (KOR) (Trescot et al., 2008, page, S134). A recent discovery of nociceptin receptor (NOR) has shown to have similar activity and effects as that of opioids, however because they are not countered by opioid antagonist, they are classified as an opioid-like receptor (Pathan & Williams, 2012, page, 12). Opioids can be agonist, partial agonist (mixed agonist-antagonist), or antagonists (Trescot et al., 2008, page, S138).
Mu receptors are located mainly in the brainstem and the medial thalamus, but work for both the central nervous system and the peripheral nervous system. (Pathan & Williams, 2012, page, 14; Trescot et al., 2008, page S134). There are two types of mu receptors: Mu1 and Mu2 receptors. Binding on Mu1 receptors gives the effects of supraspinal analgesia, bradycardia, serenity and euphoria whereas Mu2 receptors are responsible for the effects of respiratory depression, reduced gastric motility, nausea and vomiting, pruritus, dependence, prolactin release, sedation and anorexia (Trescot et al., 2008, page, S134). Mu receptors are also sometimes referred to as OP3 receptors.
Delta receptors are located primarily in the brain and their effects are still in the process of being studied (Trescot et al., 2008, page, S134). Currently we know that delta receptors can cause spinal analgesia and reduce gastric mobility (Pathan & Williams, 2012, page, 13). Delta receptors are sometimes called OP1 receptors.
Kappa receptors are found mainly in diencephalic area, limbic area, brainstem and spinal cord (Trescot et al., 2008, page, S134). Like mu receptors, they also are responsible for producing the effects of analgesia but work throughout the spinal cord (Trescot et al., 2008, page, S134). Kappa receptors also create sedation effects, dyspnea, dysphoria, diuresis, respiratory depression and dependence (Pathan & Williams, 2012, page, 13; Trescot et al., 2008, page S134). Kappa receptors are also called OP2 receptors. Out of these three receptors, most opioids act upon the agonist mu receptors (Pasternak, 2014, page, 1656).
Most opioid used for analgesia are mu receptor agonists because most delta and kappa receptor drugs are still in preclinical testing and have not been approved for clinical and therapeutic use (Pasternak, 2014, page, 1656). Pure agonist opioid receptors are the most potent analgesic receptor type because of its likeliness to produce negative effects (Trescot et al., 2008, page, S137). This is due to the fact that agonists do not have a ceiling cutoff on their activity and therefore can accumulate the drug in the human body to high toxicity levels (Pasternak, 2014, page, 1656). Most medical opioids use a mix of agonist-antagonist to reduce the risk of toxicity and side effects because these agents do have a ceiling in their analgesic effects (Trescot et al., 2008, page, S138). Antagonist are used for the reversal of agonist and have been used to help with withdrawal symptoms (Lanier & Kharasch, 2009, page, 572). Some endogenous agonists have shown to have cross-linked effects upon other receptors (Pathan & Williams, 2012, page, 12). The two most well-known antagonist opioids are naloxone and naltrexone. Naloxone is used for immediate reversal of sedation and respiratory depression due to its rapid onset of action, whereas naltrexone is used for long-term reversal because it aids in detoxification and maintenance treatment for addiction and tolerance (Lanier & Kharasch, 2009, page, 572; Trescot et al., 2008, page, S139-S140). Both antagonists are competitive inhibitors for all three receptors but share a higher affinity to mu receptors (Trescot et al., 2008, page, S140).
The three classic opioid receptors are found in many organ systems within the body that produces different responses upon activation even when binding to the same receptor. The opioid ligands derive from three precursor hormones: proenkephalin, prodynorphin, and pro-opiomegancortin which convert upon activation to enkephalin, dynorphins, and beta-endorphins respectively (Pathan & Williams, 2012, page, 12; Pasternak, 2014, page, 1655). These precursor hormones cleave a portion of amino acids to activate them.
Each receptor is structured as a 7-transmembrane receptor used for G-protein coupled activation (Pathan & Williams, 2012, page, 13; Pasternak, 2014, page, 1658). Upon binding of a ligand to the C-terminal on the extracellular side of the plasma membrane, activation of the receptor exchanges GDP for GTP intracellularly, which activates the G-protein (Pathan & Williams, 2012, page, 13; Pasternak, 2014, page, 1658). G-proteins possess 3 subunits: alpha, beta, and gamma. Active G-protein and alpha subunit separates from the beta-gamma complex and relays to a nearby protein receptor to activate phosphorylation (Pathan & Williams, 2012, page, 13; Pasternak, 2014, page, 1658). Phosphorylation of different secondary messengers causes different responses in the body including a significant decrease in adenylyl cyclase (Pathan & Williams, 2012, page, 13; Trescot et al., 2008, page, S135). Opioid receptor activation also causes activation of potassium channels and inhibition of calcium channels (Pasternak, 2014, page, 1658). All three of these effects inhibits and reduces the amount of cAMP, a secondary messenger which activates protein kinases, regulates gene expression and reduces the number of neurotransmitters released into the neural synaptic clefts (Pathan & Williams, 2012, page, 13).
In the brain, the hypothalamus is responsible for the release of the neurotransmitter hormone corticotrophin-releasing hormone (CRH) in response to stress (Stephan & Parsa, 2016, page, 63). Naturally in the body, CRH stimulates small basophilic proteins activation to produce beta-endorphin which act upon mu opioid receptors to produce different physiological effects until an accumulation of the effects causes a negative feedback loop to inhibit beta-endorphin (Stephan & Parsa, 2016, page, 63).
The physiological effects come from activation of receptors to inhibit the release of gamma-Aminobutyric acid (GABA) (Stephan & Parsa, 2016, page, 63). GABA is responsible for inhibition of tachykinin, the protein that involves in the transmission of pain in the peripheral nervous system (Stephan & Parsa, 2016, page, 63). Glutamate, substance P, and calcitonin are among the few neurotransmitters that releases the signal for pain in neurons (Trescot et al., 2008, page, S137). In the central nervous system, GABA normally inhibits the release of a different hormone, dopamine, that is in charge for the effects of pleasure. When opioid binds to beta-endorphin, GABA release is inhibited which leads to an overproduction of dopamine and increased dopamine binding leading to the overexpression of euphemism (Stephan & Parsa, 2016, page, 63). The overall effects give a feeling of wellbeing, decreased pain, and euphoria (Stephan & Parsa, 2016, page, 63).
Opioids also act as antagonists to N-methyl-D-aspartate (NMDA) receptors (Trescot et al., 2008, page, S137). This receptor is responsible for the activation of serotonin and noradrenaline through pain pathways signaled from the brain stem (Trescot et al., 2008, page, S137). Repeated stimulation of the NMDA receptors from frequent opioid use may produce opposite effects of neuropathic pain and development of tolerance towards the drug rather than analgesia (Trescot et al., 2008, page, S137). Exogenous opioids like heroin or morphine are powerful and can damage the analgesic effects when binding to endogenous binding receptors leading to prolonged and increased intensity of pain.
Rapid acting oral opioid has an onset of action as fast as 10 minutes with a duration of action of up to 4 hours whereas long acting opioids can begin action as fast as 30 minutes and can last up to 72 hours in the body depending on the condition it is used to treat (Brady et al., 2016, page, 20). The pharmacokinetics depend on the person as well as factors such as gender, age, diet, disease status, and frequency of use as well as the route of administration (Trescot et al., 2008, page, S141). Clearance and half-life of opioids depends on the drug itself, but changes in the half-life of the substance has shown to increase with more frequent use over a longer accumulation period (Trescot et al., 2008, page, S150). Intravenous injections bypass first pass metabolism to give a 100% bioavailability of the drug into the body system, and works within minutes of injection whereas oral route may not be as effective because less drug is absorbed into the circulatory system and it takes longer for the opioids to take effect (Pasternak, 2014, page, 1657). Oral route is advantageous to reduce risk of toxicity and addiction. Despite the different routes of the opioids, the desired effects are similar in that they produce the same effect of analgesia, sedation, and euphoria.
WITHDRAWAL SYMPTOMS
However, continuous or repeated daily administration of opioids can lead to harmful side effects even if the purpose is for medical therapy use. Higher dosage and more frequent administration can lead a person to develop a tolerance or physical dependency of opioids (Brady et al., 2016, page, 18). Tolerance is developed against the effects of the drug, therefore requires higher drug dosage to achieve the same amount of effect of analgesia or euphoria. Tolerance of opioid effects do not work in the same timely manner but the adverse effects does cause a decrease in therapeutic kinetics (Pasternak, 2014, page, 1657). Physical dependence is defined by withdrawal symptoms when opioids are ceded from use (Brady et al., 2016, page, 18).
Short term use is reversible with antagonist and abstinence from opioids, however longer periods of use cannot be treated the same way. Common side effects include nausea, vomiting, constipation, pruritus, miosis, dysphoria, muscular rigidity, and urinary retention (Pathan & Williams, 2012, page, 14). These symptoms usually develop after more than 2 to 3 weeks of continuous daily administration of opioids is completely terminated (Brady et al., 2016, page, 19). The most worrisome negative effect is respiratory depression (Lanier & Kharasch, 2009, page, 573). Respiratory depression constricts and abstracts airways causes a reduction in respiratory rate (Pathan & Williams, 2012, page, 14). Unconsciousness and respiratory depression from opioid overdose can lead to death (Brady et al., 2016, page, 20).
OVERDOSE
The main problem with opioids continues to be the misuse and abuse of the substance. Since the late 1990s, opioid misuse and abuse cases have rapidly increased in the United States. The 2012 National Survey on Drug Use and Health reported 12.5 million cases reported on opioid abuse (Brady et al., 2016, page, 19). Hospital admissions to treat opioid dependency increased from 2000 to 2010 by over five folds (Brady et al., 2016, page, 19). Many people do not see the problem until it gets to a point where it is hard to treat and reverse. The effects of euphoria and loss of consciousness drives people towards misuse and abuse of opioid drugs (Pathan & Williams, 2012, page, 14).
Opioid misuse is defined as any form of use outside of proper medically parameters. These include but are not limited to self-medication for anxiety or insomnia, misunderstood instruction or frequency of drug administration, or compulsive use from diagnosed opioid use condition (Brady et al., 2016, page et al., 2016, page, 19). Whereas abuse is more specific in that it is any use of the substance that is not prescribed by a medical professional, and only used for experience of euphoria (Brady et al., 2016, page, 19). When strong substances like opioids are used with frequently administered daily dosing, the human body system begins to develop a tolerance to the opioid effects. This requires higher doses to give the same amount of effect (Pasternak, 2014, page, 1657). Higher doses over long periods of time begin to give the body a required sense of dependence on the substance (Brady et al., 2016, page, 18; Lanier & Kharasch, 2009, page 572). Dependency of the drug leads to abuse and misuse of the drug including prescription forgery, stealing other patient’s opioid medications, and obtaining prescription opioids from non-medical sources (Brady et al., 2016, page, 26).
Abuse of prescription opioids has led to addiction in some patients. Addiction is characterized by the negative psychological response to withdrawal symptoms (Lanier & Kharasch, 2009, page, 572). Addiction has led to social behavior problems like accidents, suicide, and overdose which later leads to death. (Lanier & Kharasch, 2009, page, 573; Pasternak, 2014, page, 1657).
The National Survey on Drug Use and Health showed a significant increase in the rate of almost four folds for accidental prescription overdose due to opioids between 2000 and 2010 (Brady et al., 2016, page, 21). Opioid overdose deaths exceed number of deaths caused by overdose of any other category of drugs (Brady et al., 2016, page, 19). It is estimated about 16,651 deaths by opioid addiction in 2010 and increased to an estimate of 16,235 deaths in 2013 (Stephan & Parsa, 2016, page, 63). Overdose and opioid abuse is statistically more likely to occur in younger adults (18-25 years of age), males, nicotinic users, patients who have a history of substance abuse in the past, those diagnosed with psychiatric disorders or depression, and those who have fairly high dosage of prescribed opioids (Brady et al., 2016, page, 20).
Because this is one of the biggest problem in the pharmaceutical field, the Office of National Drug Control Policy has recommended strategies to prevent and reduce opioid abuse (Brady et al., 2016, page, 21). The main key recommendations include patient education on risk factors of misuse and abuse, enhance prescription monitoring, stricter therapeutic guidelines, closer monitoring and screening of therapy, proper disposal of drugs, and addressing diversions like doctor shopping by stronger enforcements (Brady et al., 2016, page, 21). Physicians have started opioid rotation in cancer patients to reduce the chances of developing strong dependency and tolerance (Pasternak, 2014, page, 1657).
While opioids have been a very good source of pain relief and pain management for severe conditions like cancer, they have the potential to be abused and can lead to social problems like addiction, therefore opioid use should be strictly monitored to legal properly prescribed medications.