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An opiate is an alkaloid substance derived from opium (or poppy straw). It differs from the similar term opioid in that the latter is used to designate all substances, both natural and synthetic, that bind to opioid receptors in the brain (including antagonists). Opiates are alkaloid compounds naturally found in the opium poppy plant Papaver somniferum.
In 2014, between 13 and 20 million people used opioids recreationally, representing 0.3% to 0.4% of the global population between the ages of 15 and 65. According to the CDC, from this population, there were 47,000 deaths, with a total of 500,000 deaths from 2000 to 2014. In 2016, the World Health Organization reported that 27 million people suffer from opioid use disorder. They also reported that in 2015, 450,000 people died as a result of drug use, with between a third and a half of that number being attributed to opioids.
Very small quantities of hydrocodone and hydromorphone are detected in assays of opium on rare occasions. It appears to be produced by the plant under circumstances and by processes that are not understood at this time. Dihydrocodeine, oxymorphol, oxycodone, oxymorphone, metopon Possibly other derivatives of morphine and/or hydromorphone also are found in trace amounts in opium.
Despite morphine being the most medically significant opioid, larger quantities of codeine are consumed medically, most of it synthesized from morphine. Codeine has greater and more predictable oral bioavailability. Codeine is not reliably metabolised into its active form, morphine, by CYP2D6 due to the considerable amount of polymorphism. Many individuals lack any appreciable metabolism to morphine and experience no therapeutic effects, although may still have nausea/vomiting or constipation.
A significant population are rapid, or ultra-rapid metabolizers and can quickly develop fatal toxicity from even the small amount present in breast milk or from a few doses. It is widely thought that Codeine has less abuse potential than morphine, in spite of widely being abused. Its abuse potential is largely limited by its adverse effect profile. Use of codeine in many countries is decreasing because of the wide range of metabolism, frequent adverse effects at therapeutic (30 to 60mg doses) doses, and in most people its analgesic efficacy is comparable to a therapeutic dose of acetaminophen.
Opiate withdrawal syndrome effects are associated with the abrupt cessation or reduction of prolonged opiate usage.
The manifestation of opiate dependence and abuse relies on a variety of factors, including the opiate's pharmacokinetic properties and the user's predisposition for addiction.
In 2015 researchers reported successful biosynthesis of thebaine and hydrocodone using genetically modified yeast. Once scaled for commercial use, the process would cut production time from a year to several days and could reduce costs by 90%.
Morphine is metabolized in the liver to morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), and are excreted by the kidneys. It is are also able to cross into the blood-brain barrier into the cerebrospinal fluid. M6G has potent analgesic activity, binds to opioid receptors, and is a main contributor to the therapeutic benefit of morphine. M3G does not act as an analgesic, has a low affinity for opioid receptors, and may possibly antagonize the therapeutic effects of morphine and M6G. Moreover, high doses of morphine, and thus M3G, are associated with neurotoxic side effects such as hyperalgesia, allodynia and myoclonus.
In spite of scarce, often conflicting, evidence, at times studies showing no benefit at all, opioids such as codeine, hydrocodone, and hydromorphone have been traditionally used for treatment of acute viral cough (aka "acute bronchitis"), cough due to COPD exacerbation, chronic post-viral cough, chronic idiopathic cough, and cough from other causes. Given the abuse potential, the frequent GI side effects, and several studies showing no discernable benefit, recommendations are against use of opioids for cough in children.
In spite of widespread use, the science supporting use of opioids for cough in adults is most notable for the small sample size, poor study design, and inconclusive results which suggest that there may be a small reduction in the amount of coughing when it is precisely measured. Actual evidence of patient-oriented outcomes, e.g. do the patients feel any better than when given a placebo, is elusive. The use of codeine as the "gold-standard" for which other drugs can be compared has been called into question, as showing that a drug is as good as, or at least not worse than, a drug with no benefit and only noxious side effects and a potential for abuse leaves much to be desired.
Opioid dose conversions may be necessary when switching medications given the differing pharmacodynamics between opioids. Generally, parenteral (IV or IM) morphine is used as the standard for converting between opiates to achieve equivalent analgesic effects. These differences in morphine-equivalents may differ between formulations of the same medication, and certainly between oral and injection. Calculating total daily dose using morphine milligram equivalents is used to identify patients at risk of overdose.
While overdose, whether intentional, accidental, or due to rapid 2D6 conversion of codeine (or tramadol, a non-opiate opioid that, like codeine, has little intrinsic effect on μ-receptors, but rather acts as pro-drug with an active metabolite that is a μ-agonist.
Less common side effects include: delayed gastric emptying, hyperalgesia, immunologic and hormonal dysfunction (hypogonadism is often seen in men taking chronic opioids, but is not always clinically evident), muscle rigidity, and myoclonus.
Opiate use for pain is widely accepted in the healthcare system. Long-term treatment for chronic pain is controversial as there is a high risk of addiction associated with its use leading to Substance abuse and diversion to others even when taken properly. Those addicted to opiates will prioritize acquiring these drugs over other activities in their lives, negatively impacting their professional and personal relationships. Moreover, there are not many well-designed studies evaluating the overall safety and efficacy. Many small studies using small doses, often half the recommended dose, have not shown much effect, but these cannot be relied upon to give much information on the more common practice of step-wise therapy and slow dose escalation.
Chronic opioid use predictably leads to Drug tolerance, and may do so fairly quickly, in days to weeks. This occurs even with what are considered modest doses, e.g. ≥25mg oxycodone a day. This may result in the patient to need higher and/or more frequent doses of the drug to get euphoric effects, although it may not be a factor in analgesic effects as tolerance to a dose of opioid does not seem related to loss of efficacy. Tolerance is associated with upregulation of μ-receptors, and possibly others.
Concentration-dependence adverse effects may vary based on the user's genetic polymorphisms which can alter drug metabolism. Cytochrome P450, notably CYP2D6, but also CYP3A4, is responsible for the metabolism of various opiates to active metabolites and variations in CYP450 activity lead to varying serum drug levels.
More than 70% of opioid receptors are μ receptors, predominantly located on the central terminals of nociceptors in the dorsal horn of the spinal cord. The remaining 30% of opioid receptors are located post-synaptically on dendrites of second-order spinothalamic neurons & interneurons.
When an opiate binds as an agonist to the GPCR, there will be a signaling cascade resulting in the inhibition of adenylate cyclase and calcium ion channels with the stimulation of potassium ion channels. The net effect of these changes is a reduced intracellular cAMP and hyperpolarization of the neuronal cell reducing neurotransmitter release. Through this pathway, when opiates bind to and activate the mu receptor, there is a decrease transmission of pain signalling.
This pathway targeted for the analgesia properties that opiates are known and used for. Other clinically important roles of mu are its involvement in respiratory and cardiovascular functions, gastrointestinal peristalsis, feeding, and mood. These other pathways are important because they explain the side effects of opiate use like respiratory depression at high doses, constipation with chronic use, and addicting properties.
Statistically, middle-aged patients with substance use history and psychiatric comorbidities are seen with higher mortality risks such as suicide.
Iatrogenesis physiological and psychological drug dependence can occur to one of any background. Some physicians are more liberal with their prescribing of opiates and their patients become dependent on opiates by simply following their doctor's orders.
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