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98-551: Codeine is an opiate and prodrug of morphine mainly used to treat pain , coughing , and diarrhea . It is also commonly used as a recreational drug . It is found naturally in the sap of the opium poppy , Papaver somniferum . It is typically used to treat mild to moderate degrees of pain. Greater benefit may occur when combined with paracetamol (acetaminophen) or a nonsteroidal anti-inflammatory drug (NSAID) such as aspirin or ibuprofen . Evidence does not support its use for acute cough suppression in children. In Europe, it

196-405: A 30 mg dose could yield up to 4 mg of morphine. While codeine can be directly extracted from opium, its original source, most codeine is synthesized from the much more abundant morphine through the process of O- methylation , through a process first completed in the late 20th century by Robert C. Corcoran and Junning Ma. Codeine has been used in the past as the starting material and prototype of

294-451: A barrier which is usually a type of polymer. Diffusion systems can be broken into two subcategories, reservoir devices and matrix devices. Dissolution systems must have the system dissolved slowly in order for the drug to have sustained release properties which can be achieved by using appropriate salts and/or derivatives as well as coating the drug with a dissolving material. It is used for drug compounds with high solubility in water. When

392-469: A broad therapeutic window is necessary to avoid toxicity; otherwise, the risk is unwarranted and another mode of administration would be recommended. Appropriate half-lives used to apply sustained methods are typically 3–4 hours and a drug dose greater than 0.5 grams is too high. The therapeutic index also factors whether a drug can be used as a time release drug. A drug with a thin therapeutic range, or small therapeutic index, will be determined unfit for

490-455: A constant drug concentration for a specific period of time with minimum side effects . This can be achieved through a variety of formulations, including liposomes and drug-polymer conjugates (an example being hydrogels ). Sustained release's definition is more akin to a "controlled release" rather than "sustained". Extended-release dosage consists of either sustained-release (SR) or controlled-release (CR) dosage. SR maintains drug release over

588-411: A contraindication to use. Codeine is used to relieve coughing . Evidence does not support its use for acute cough suppression in children. In Europe, it is not recommended as a cough medicine in those under 12 years of age. Some tentative evidence shows it can reduce a chronic cough in adults. It is used to treat diarrhea and diarrhea-predominant irritable bowel syndrome , although loperamide (which

686-512: 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 )

784-407: 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

882-460: A half-life of three to four hours. It is hepatically metabolized to the active metabolites of normeperidine, normepiridinic acid, and medperidinic acid. Normeperidine may accumulate to toxic levels in patients with renal impairment with repeated doses, and can cause CNS excitation and seizures. Methadone has a higher bioavailability and half-life compared to morphine. It is metabolized to an inactive product by N-demethylation by CYP3A4 enzymes in

980-418: A high first-pass metabolism when given orally, and is primarily glucuronidated in the liver to hydromorphone-3-glucoronide (H3G). 75% of hydromorphone is renally excreted, with 7% excreted as the parent opiate. Meperidine is a synthetic opiate, part of the arylpiperidine class. It is a strong μ-r eceptor agonist with one-tenth the potency of morphine. Historically, it has been used to treat rigors, and has

1078-683: A large class of mainly mild to moderately strong opioids; such as hydrocodone (1920 in Germany), oxycodone (1916 in Germany), dihydrocodeine (1908 in Germany), and its derivatives such as nicocodeine (1956 in Austria). However, these opioids are no longer synthesized from codeine and are usually synthesized from other opium alkaloids; specifically thebaine . Other series of codeine derivatives include isocodeine and its derivatives, which were developed in Germany starting around 1920. In general,

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1176-468: A lesser extent. To minimize withdrawal symptoms, long-term users should gradually reduce their codeine medication under the supervision of a healthcare professional. Also, no evidence indicates that CYP2D6 inhibition is useful in treating codeine dependence, though the metabolism of codeine to morphine (and hence further metabolism to glucuronide morphine conjugates) does have an effect on the abuse potential of codeine. However, CYP2D6 has been implicated in

1274-405: A matter of days in patients who have multiple functional alleles of CYP2D6, resulting in ultrarapid metabolism of opioids such as codeine into morphine. Studies on codeine's analgesic effect are consistent with the idea that metabolism by CYP2D6 to morphine is important, but some studies show no major differences between those who are poor metabolizers and extensive metabolizers. Evidence supporting

1372-431: 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

1470-650: A number of which were popular in England since the beginning of the 18th century; the original preparation seems to have been elaborated in Leiden , the Netherlands around 1715 by a chemist Jakob Le Mort; in 1721 the London Pharmacopoeia mentions an Elixir Asthmaticum, replaced by the term Elixir Paregoricum ("pain soother") in 1746. The progressive isolation of opium's several active components opened

1568-418: A patent in 1938 by Israel Lipowski, who coated pellets which led to coating particles. The science of controlled release developed further with more oral sustained-release products in the late 1940s and early 1950s, the development of controlled release of marine anti-foulants in the 1950s, and controlled release fertilizer in the 1970s where sustained and controlled delivery of nutrients was achieved following

1666-519: 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

1764-543: A prescription as a time release tablet . Codeine is also marketed in cough syrups with zero to a half-dozen other active ingredients, and a linctus ( e.g., Paveral) for all of the uses for which codeine is indicated. Injectable codeine is available for subcutaneous or intramuscular injection only; intravenous injection is contraindicated, as this can result in nonimmune mast-cell degranulation and resulting anaphylactoid reaction. Codeine suppositories are also marketed in some countries. Common adverse effects associated with

1862-505: A salt in the form of either codeine sulfate or codeine phosphate in the United States, United Kingdom and Australia. Codeine hydrochloride is more common worldwide and the citrate, hydroiodide, hydrobromide, tartrate, and other salts are also seen. The chemical name for codeine is morphinan-6-ol, 7,8-didehydro-4,5-epoxy-3-methoxy-17-methyl-, (5α,6α)- A heroin (diamorphine) or other opiate / opioid addict may use codeine to ward off

1960-442: A slower rate without worry of excreting it. This system requires that there are enough gastric fluids present as well as food. Many types of forms of drugs use this method such as powders, capsules, and tablets. Bio-adhesive systems generally are meant to stick to mucus and can be favorable for mouth based interactions due to high mucus levels in the general area but not as simple for other areas. Magnetic materials can be added to

2058-519: A sustained period but not at a constant rate. CR maintains drug release over a sustained period at a nearly constant rate. Sometimes these and other terms are treated as synonyms, but the United States Food and Drug Administration has in fact defined most of these as different concepts. Sometimes the term "depot tablet" is used, by analogy to the term for an injection formulation of a drug which releases slowly over time , but this term

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2156-405: A sustained release mechanism in partial fear of dose dumping which can prove fatal at the conditions mentioned. For a drug that is made to be released over time, the objective is to stay within the therapeutic range as long as needed. There are many different methods used to obtain a sustained release. Diffusion systems' rate release is dependent on the rate at which the drug dissolves through

2254-458: 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. While the full synthesis of opioids from naphthoquinone (Gates synthesis) or other simple organic starting materials

2352-543: 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. Opiates belong to the large biosynthetic group of benzylisoquinoline alkaloids , and are so named because they are naturally occurring alkaloids found in

2450-416: A year to several days and could reduce costs by 90%. Codeine is a prodrug which is converted to morphine and acts on μ -opiate receptors. It is converted to morphine by metabolism of CYP2D6 enzymes. Individuals who have lower CYP2D6 activity may not metabolize codeine at all, and will not experience its analgesic effects. Conversely, individuals with rapid or ultra-rapid CYP2D6 activity may metabolize

2548-422: Is a mechanism that (in contrast to immediate-release dosage ) delivers a drug with a delay after its administration (delayed-release dosage) or for a prolonged period of time (extended-release [ER, XR, XL] dosage) or to a specific target in the body (targeted-release dosage). Sustained-release dosage forms are dosage forms designed to release (liberate) a drug at a predetermined rate in order to maintain

2646-475: Is a nonsynthetic opioid . It is a selective agonist of the μ-opioid receptor (MOR). Codeine itself has relatively weak affinity for the MOR. Instead of acting directly on the MOR, codeine functions as a prodrug of its major active metabolites morphine and codeine-6-glucuronide , which are far more potent MOR agonists in comparison. Codeine has been found as an endogenous compound, along with morphine, in

2744-539: 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

2842-459: Is also commonly marketed in products containing codeine with other pain killers or muscle relaxers, as well as codeine mixed with phenacetin (Emprazil with codeine No. 1, 2, 3, 4, and 5), naproxen , indomethacin , diclofenac , and others, as well as more complex mixtures, including such mixtures as aspirin + paracetamol + codeine ± caffeine ± antihistamines and other agents, such as those mentioned above. Codeine-only products can be obtained with

2940-473: Is also regarded as a more complete technology to produce complex dissolution profiles. Through coating an active pharmaceutical ingredient around an inert core and layering it with insoluble substances to form a microsphere, one can obtain more consistent and replicable dissolution rates in a convenient format that can be mixed and matched with other instant release pharmaceutical ingredients into any two piece gelatin capsule . There are certain considerations for

3038-457: Is an alkaloid found in the opium poppy , Papaver somniferum var. album , a plant in the family Papaveraceae . Opium poppy has been cultivated and utilized throughout human history for a variety of medicinal (analgesic, anti-tussive and anti-diarrheal ) and hypnotic properties linked to the diversity of its active components, which include morphine, codeine and papaverine . Codeine is found in concentrations of 1% to 3% in opium prepared by

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3136-640: Is available without a prescription for milder diarrhea), diphenoxylate , paregoric , or even laudanum are more frequently used to treat severe diarrhea. Codeine is marketed as both a single-ingredient drug and in combination preparations with paracetamol (as co-codamol : e.g., brands Paracod, Panadeine, and the Tylenol-with-codeine series, including Tylenol 3 and 1, 2, and 4); with aspirin (as co-codaprin ); or with ibuprofen (as Nurofen Plus ). These combinations provide greater pain relief than either agent alone ( drug synergy ). Codeine

3234-492: Is available. The CPIC also suggests that codeine use be avoided in poor metabolizers, due to its lack of efficacy in this group. Codeine and its salts are readily absorbed from the gastrointestinal tract, and ingestion of codeine phosphate produces peak plasma concentrations in about one hour. Plasma half life is between 3 and 4 hours, and oral/intramuscular analgesic potency ratio is approximately equal to 1:1.5. The most common conversion ratio, given on equianalgesia charts used in

3332-554: Is dose-related and is a mechanism for the potentially fatal consequences of overdose. As codeine is metabolized to morphine, morphine can be passed through breast milk in potentially lethal amounts, fatally depressing the respiration of a breastfed baby. In August 2012, the United States Food and Drug Administration issued a warning about deaths in pediatric patients less than 6 years old after ingesting "normal" doses of paracetamol with codeine after tonsillectomy; this warning

3430-399: Is formed by the acetylation of morphine in order to increase the lipid solubility. Heroin (diacetylmorphine) is a morphine prodrug ; it is metabolized by the liver into morphine after administration. One of the major metabolites of heroin, 6-monoacetylmorphine (6-MAM), is also a morphine prodrug. Hydromorphone is derived from morphine and may be used as an alternative to it. It has

3528-443: Is important to note that codeine usage results in significant amounts of morphine as an excretion product. Furthermore, heroin contains codeine (or acetyl codeine) as an impurity and its use will result in excretion of small amounts of codeine. Poppy seed foods represent yet another source of low levels of codeine in one's biofluids . Blood or plasma codeine concentrations are typically in the 50–300 μg/L range in persons taking

3626-448: Is metabolized in the liver to morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), and are excreted by the kidneys. It is 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

3724-475: Is needed if the user responds negatively. As with other opiates, chronic use of codeine can cause physical dependence which can lead to severe withdrawal symptoms if a person suddenly stops the medication. Withdrawal symptoms include drug craving, runny nose, yawning, sweating, insomnia, weakness, stomach cramps, nausea, vomiting, diarrhea, muscle spasms, chills, irritability, and pain. These side-effects also occur in acetaminophen/aspirin combinations, though to

3822-475: Is no industry standard for these abbreviations, and confusion and misreading have sometimes caused prescribing errors. Clear handwriting is necessary. For some drugs with multiple formulations, putting the meaning in parentheses is advisable. A few other abbreviations are similar to these (in that they may serve as suffixes) but refer to dose rather than release rate. They include ES and XS (Extra Strength). Today, most time-release drugs are formulated so that

3920-593: Is not medically or pharmaceutically standard for oral medication. Modified-release dosage and its variants are mechanisms used in tablets (pills) and capsules to dissolve a drug over time in order to be released more slowly and steadily into the bloodstream, while having the advantage of being taken at less frequent intervals than immediate-release (IR) formulations of the same drug. For example, orally administered extended-release morphine can enable certain chronic pain patients to take only 1–2 tablets per day, rather than needing to redose every 4–6   hours as

4018-558: Is not recommended as a cough medicine in those under 12 years of age. It is generally taken by mouth. It typically starts working after half an hour, with maximum effect at two hours. Its effects last for about four to six hours. Codeine exhibits abuse potential similar to other opioid medications, including a risk of addiction and overdose . Common side effects include vomiting , constipation , itchiness , lightheadedness , and drowsiness . Serious side effects may include breathing difficulties and addiction. Whether its use in pregnancy

Codeine - Misplaced Pages Continue

4116-440: 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

4214-426: Is possible, they are tedious and uneconomical processes. Therefore, most of the opiate-type analgesics in use today are either extracted from Papaver somniferum or synthesized from those opiates, especially thebaine . 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

4312-567: Is represented by the Controlled Release Society (CRS). The CRS is the worldwide society for delivery science and technologies. CRS serves more than 1,600 members from more than 50 countries. Two-thirds of CRS membership is represented by industry and one-third represents academia and government. CRS is affiliated with the Journal of Controlled Release and Drug Delivery and Translational Research scientific journals. There

4410-496: Is responsible for a large percentage of the analgesia of codeine, and thus these patients should experience some analgesia. Many of the adverse effects will still be experienced in poor metabolizers. Conversely, between 0.5% and 2% of the population are "extensive metabolizers"; multiple copies of the gene for 2D6 produce high levels of CYP2D6 and will metabolize drugs through that pathway more quickly than others. Some medications are CYP2D6 inhibitors and reduce or even completely block

4508-770: Is responsible for the metabolism of various opiates to active metabolites and variations in CYP450 activity lead to varying serum drug levels. Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage. It is an essential defensive function where pain works as an alarm to avoid or limit tissue damage. Its neurobiology is complex, and involves stimulation of several different types of nerves. Opioids act upon opioid receptors that are coupled to inhibitor G protein coupled receptors (GPCR). These receptors fall into 3 classes: μ (mu) , δ (delta) , and κ (kappa) receptors. More than 70% of opioid receptors are μ receptors, predominantly located on

4606-482: Is safe is unclear. Care should be used during breastfeeding , as it may result in opiate toxicity in the baby. Its use as of 2016 is not recommended in children. Codeine works following being broken down by the liver into morphine; how quickly this occurs depends on a person's genetics . Codeine was discovered in 1832 by Pierre Jean Robiquet . In 2013, about 361,000 kg (795,000 lb) of codeine were produced while 249,000 kg (549,000 lb) were used, which made it

4704-491: Is typical with standard-release morphine tablets. Most commonly it refers to time-dependent release in oral dose formulations. Timed release has several distinct variants such as sustained release where prolonged release is intended, pulse release, delayed release (e.g. to target different regions of the GI tract) etc. A distinction of controlled release is that it not only prolongs action, but it attempts to maintain drug levels within

4802-465: Is used as a continual drug (e.g. transdermal patches, longer term use of IV fentanyl in ICU patients) its elimination half-life and duration of effect are longer than morphine. It is metabolized in the liver by CYP3A4 enzymes to the compound norfentanyl. Heroin, the common name for diacetylmorphine , is the first of several semi-synthetic opioids to be derived from morphine, a component of natural opium. It

4900-590: Is used to identify patients at risk of overdose. Common side effects associated with opioid use include: sedation , nausea , dizziness, vomiting, constipation , physical dependence, tolerance, and potentially fatal respiratory depression . Of these the most common are constipation & nausea. There is no development of tolerance to constipation. This is why stool softeners or laxatives (polyethylene glycol, docusate, and senna) are often prescribed with opioids. While overdose, whether intentional, accidental, or due to rapid 2D6 conversion of codeine (or tramadol,

4998-471: Is widely accepted in the healthcare system. However, long-term treatment for chronic pain is controversial as there is a high risk of addiction associated with its use leading to 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

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5096-418: The active ingredient is embedded in a matrix of insoluble substance(s) (various: some acrylics , even chitin ; these substances are often patented ) such that the dissolving drug must find its way out through the holes. In some SR formulations, the drug dissolves into the matrix, and the matrix physically swells to form a gel, allowing the drug to exit through the gel's outer surface. Micro-encapsulation

5194-629: The therapeutic window to avoid potentially hazardous peaks in drug concentration following ingestion or injection and to maximize therapeutic efficiency. In addition to pills, the mechanism can also apply to capsules and injectable drug carriers (that often have an additional release function), forms of controlled release medicines include gels, implants and devices (e.g. the vaginal ring and contraceptive implant ) and transdermal patches . Examples for cosmetic, personal care, and food science applications often centre on odour or flavour release. The release technology scientific and industrial community

5292-545: The European Union member states, 11 countries (Bulgaria, Cyprus, Denmark, Estonia, Ireland, Latvia, Lithuania, Malta, Poland, Romania, Slovenia) allow the sale of OTC codeine solid dosage forms. Opiate In 2014, between 13 and 20 million people used opioids recreationally (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

5390-435: The GI tract due to prolonged release of irritating drugs from the non-deformable tablet. In the ion-exchange method, the resins are cross-linked water-insoluble polymers that contain ionisable functional groups that form a repeating pattern of polymers, creating a polymer chain. The drug is attached to the resin and is released when an appropriate interaction of ions and ion exchange groups occur. The area and length of

5488-480: The United States, Canada, the UK, Republic of Ireland, the European Union, Russia and elsewhere as 130 mg IM equals 200 mg PO—both of which are equivalent to 10 mg of morphine sulphate IV and 60 mg of morphine sulphate PO. The salt:freebase ratio of the salts of both drugs in use are roughly equivalent, and do not generally make a clinical difference. Codeine is metabolised by O - and N -demethylation in

5586-399: 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

5684-414: 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, and 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

5782-414: The brains of nonhuman primates with depolarized neurons, indicating that codeine may function as a neurotransmitter or neuromodulator in the central nervous system. Like morphine, codeine causes TLR4 signaling which causes allodynia and hyperalgesia . It does not need to be converted to morphine to increase pain sensitivity. Codeine is an opiate and an agonist of the mu opioid receptor (MOR). It acts on

5880-417: The central nervous system to have an analgesic effect. It is metabolised in the liver to produce morphine which is ten times more potent against the mu receptor. Opioid receptors are G protein-coupled receptors that positively and negatively regulate synaptic transmission through downstream signalling. Binding of codeine or morphine to the mu opioid receptor results in hyperpolarization of the neuron leading to

5978-507: 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

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6076-594: The conversion of codeine to morphine. The best-known of these are two of the selective serotonin reuptake inhibitors , paroxetine (Paxil) and fluoxetine (Prozac) as well as the antihistamine diphenhydramine (Benadryl) and the antidepressant bupropion (Wellbutrin, also known as Zyban). Other drugs, such as rifampicin and dexamethasone , induce CYP450 isozymes and thus increase the conversion rate. CYP2D6 converts codeine into morphine, which then undergoes glucuronidation. Life-threatening intoxication, including respiratory depression requiring intubation, can develop over

6174-423: The correct composition in 1853 but a chemical structure was proposed only in 1925 by J. M. Gulland and Robert Robinson . The first crystal structure would have to wait until 1954. Codeine and morphine, as well as opium, were used in an attempt to treat diabetes in the 1880s and thereafter, as recently as the 1950s. Numerous codeine salts have been prepared since the drug was discovered. The most commonly used are

6272-443: The drug is covered with some slow dissolving coat, it will eventually release the drug. Instead of diffusion, the drug release depends on the solubility and thickness of the coating. Because of this mechanism, the dissolution will be the rate limiting factor for drug release. Dissolution systems can be broken down to subcategories called reservoir devices and matrix devices. Osmotic controlled-release oral delivery systems (OROS) have

6370-462: The drug release and number of cross-link polymers dictate the rate at which the drug is released, determining the SR effect. A floating system is a system where it floats on gastric fluids due to low density. The density of the gastric fluids is about 1 g/mL; thus, the drug/tablet administered must have a smaller density. The buoyancy will allow the system to float to the top of the stomach and release at

6468-779: The drug so another magnet can hold it from outside the body to assist in holding the system in place. However, there is low patient compliance with this system. The matrix system is the mixture of materials with the drug, which will cause the drug to slow down. However, this system has several subcategories: hydrophobic matrices, lipid matrices, hydrophilic matrices, biodegradable matrices, and mineral matrices. Examples of stimuli that may be used to bring about release include pH, enzymes, light, magnetic fields, temperature, ultrasonics, osmosis, cellular traction forces, and electronic control of MEMS and NEMS . Spherical hydrogels, in micro-size (50-600 μm diameter) with 3-dimensional cross-linked polymer, can be used as drug carrier to control

6566-401: The drug therapeutically, 700–7,000 μg/L in chronic users and 1,000–10,000 μg/L in cases of acute fatal over dosage. Codeine is produced in the human body along the same biosynthetic pathway as morphine . Urinary concentrations of endogenous codeine and morphine have been found to significantly increase in individuals taking L-DOPA for the treatment of Parkinson's disease . Around

6664-421: The drug too quickly and experience dose-related side effects such as sedation and fatal respiratory depression. Fentanyl is a synthetic piperidine opioid structurally similar to arylpiperidines. It is a strong μ-r eceptor agonist that is 80–100 times more potent than morphine, and has a fast onset with a shorter duration of action than morphine due to redistribution from CNS location to fatty tissue. When it

6762-444: The effects of withdrawal during periods where their preferred drug is unavailable or unaffordable. Codeine is also available in conjunction with the anti-nausea medication promethazine in the form of a syrup. Brand named as Phenergan with Codeine or in generic form as promethazine with codeine, it began to be mixed with soft drinks in the 1990s as a recreational drug, called 'syrup', 'lean', or ' purple drank '. Rapper Pimp C , from

6860-408: The form of a rigid tablet with a semi-permeable outer membrane and one or more small laser drilled holes in it. As the tablet passes through the body , water is absorbed through the semipermeable membrane via osmosis , and the resulting osmotic pressure is used to push the active drug through the opening(s) in the tablet. OROS is a trademarked name owned by ALZA Corporation , which pioneered

6958-434: The formation of sustained-release formulation: The biological half-life of the drug refers to the drug's elimination from the bloodstream which can be caused by metabolism, urine, and other forms of excretion. If the active compound has a long half-life (over 6 hours), it is sustained on its own. If the active compound has a short half-life, it would require a large amount to maintain a prolonged effective dose. In this case,

7056-615: The group UGK , died from an overdose of this combination. Codeine is used in illegal drug laboratories to make morphine. Codeine and its major metabolites may be quantitated in blood , plasma or urine to monitor therapy, confirm a diagnosis of poisoning or assist in a medico-legal death investigation. Drug abuse screening programs generally test urine , hair , sweat or saliva . Many commercial opiate screening tests directed at morphine cross-react appreciably with codeine and its metabolites, but chromatographic techniques can easily distinguish codeine from other opiates and opioids. It

7154-568: The hydrochloride (freebase conversion ratio 0.805, i.e. 10 mg of the hydrochloride salt is equivalent in effect to 8.05 mg of the freebase form), phosphate (0.736), sulphate (0.859), and citrate (0.842). Others include a salicylate NSAID , codeine salicylate (0.686), a bromide ( codeine methylbromide , 0.759), and at least five codeine-based barbiturates , the phenylethylbarbiturate (0.56), cyclohexenylethylbarbiturate (0.559), cyclopentenylallylbarbiturate (0.561), diallylbarbiturate (0.561), and diethylbarbiturate (0.619). The latter

7252-720: The hypothesis that ultrarapid metabolizers may get greater analgesia from codeine due to increased morphine formation is limited to case reports. Due to increased metabolism of codeine to morphine, ultrarapid metabolizers (those possessing more than two functional copies of the CYP2D6 allele) are at increased risk of adverse drug effects related to morphine toxicity. Guidelines released by the Clinical Pharmacogenomics Implementation Consortium (CPIC) advise against administering codeine to ultrarapid metabolizers, where this genetic information

7350-475: The inhibition of release of nociceptive neurotransmitters, causing an analgesic effect and increased pain tolerance due to reduced neuronal excitability. The conversion of codeine to morphine occurs in the liver and is catalyzed by the cytochrome P450 enzyme CYP2D6 . CYP3A4 produces norcodeine , and UGT2B7 conjugates codeine, norcodeine, and morphine to the corresponding 3- and 6-glucuronides. Srinivasan, Wielbo and Tebbett speculate that codeine-6-glucuronide

7448-600: The latex method from unripe pods of Papaver somniferum . The name codeine is derived from the Ancient Greek κώδεια ( kṓdeia , "poppy head"). The relative proportion of codeine to morphine, the most common opium alkaloid at 4% to 23%, tends to be somewhat higher in the poppy straw method of preparing opium alkaloids. Until the beginning of the 19th century, raw opium was used in diverse preparations known as laudanum (see Thomas de Quincey 's Confessions of an English Opium-Eater , 1821) and paregoric elixirs ,

7546-401: The liver to morphine and norcodeine. Hydrocodone is also a metabolite of codeine in humans. Codeine and its metabolites are mostly removed from the body by the kidneys, primarily as conjugates with glucuronic acid. The active metabolites of codeine, notably morphine, exert their effects by binding to and activating the μ-opioid receptor . In people that can extensively metabolize the codeine,

7644-879: The liver. It has high person-to-person variability because of varying levels of CYP3A4 in individuals. It is approved for treatment of moderate to severe pain as well as opioid dependence. Because of its high risk of drug interactions, liver toxicity, and patient variability, patients have to be monitored closely at methadone clinics . In addition, there is an increase risk of mortality in patients who are treated with methadone compared to other opioids, thought to be due to QTc prolongation and cardiac arrhythmias. Nicomorphine (Vilan, morphine dinicotinate), Diamorphine (Heroin, morphine diacetate), dipropanoylmorphine (morphine dipropionate), desomorphine (Permonid, di-hydro-desoxy-morphine), methyldesorphine , acetylpropionylmorphine , dibenzoylmorphine , diacetyldihydromorphine , and several others are also derived from morphine. Morphine

7742-423: The methyl groups at the 3 position including ethylmorphine , also known as codethyline (Dionine), and benzylmorphine (Peronine). While having no narcotic effects of its own, the important opioid precursor thebaine differs from codeine only slightly in structure. Pseudocodeine and some other similar alkaloids not currently used in medicine are found in trace amounts in opium as well. Codeine, or 3-methylmorphine,

7840-634: The microcapsules inside are swallowed whole. Among the health information technology (HIT) that pharmacists use are medication safety tools to help manage this problem. For example, the ISMP "do not crush" list can be entered into the system so that warning stickers can be printed at the point of dispensing, to be stuck on the pill bottle. Pharmaceutical companies that do not supply a range of half-dose and quarter-dose versions of time-release tablets can make it difficult for patients to be slowly tapered off their drugs. The earliest SR drugs are associated with

7938-595: The most commonly taken opiate. It is on the World Health Organization's List of Essential Medicines . Codeine occurs naturally and makes up about 2% of opium . Codeine is used to treat mild to moderate pain. It is commonly used to treat post-surgical dental pain. Weak evidence indicates that it is useful in cancer pain , but it may have increased adverse effects, especially constipation, compared to other opioids. The American Academy of Pediatrics does not recommend its use in children due to side effects. The Food and Drug Administration (FDA) lists age under 12 years old as

8036-411: The nitrogen morphine derivatives as is codeine methobromide, and heterocodeine , which is a drug six times stronger than morphine and 72 times stronger than codeine due to a small re-arrangement of the molecule, namely moving the methyl group from the 3 to the 6 position on the morphine carbon skeleton. Drugs bearing resemblance to codeine in effects due to close structural relationship are variations on

8134-587: The opium poppy. The major psychoactive opiates are morphine , codeine , and thebaine . Papaverine , noscapine , and approximately 24 other alkaloids are also present in opium but have little to no effect on the human central nervous system . Alkaloids that have no effect on the central nervous system were not always considered to be opiates, but current trend is to refer to all alkaloids derived from opium or poppy straw as such. Very small quantities of hydrocodone and hydromorphone are detected in assays of opium on rare occasions; it appears to be produced by

8232-441: 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 tolerance , and may do so fairly quickly (days to weeks). This occurs even with what are considered modest doses (e.g. ≥25mg oxycodone

8330-773: The parent drug. Oxymorphone-3-glucuronide's activity is unknown. Opiates with opioid activity are mainly used for pain management with the premise that there will be benefits for both pain & function that will outweigh the risks to the patient. Another indication is symptomatic relief of shortage of breath , both in the acute setting (for example, pulmonary edema ) and in terminally ill patients. 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

8428-551: The path to improved selectivity and safety of the opiates-based pharmacopeia. Morphine had already been isolated in Germany by Friedrich Sertürner in 1804. Codeine was first isolated in 1832 in France by Pierre Robiquet , already famous for the discovery of alizarin , the most widespread red dye, while working on refined morphine extraction processes. Robiquet is also credited with discovering caffeine independently of Pelletier, Caventou, and Runge. Thomas Anderson determined

8526-487: 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

8624-537: The release of the drug. These hydrogels are called microgels. They may possess a negative charge as example DC-beads. By ion-exchange mechanism, a large amount of oppositely charged amphiphilic drugs can be loaded inside these microgels. Then, the release of these drugs can be controlled by a specific triggering factor like pH, ionic strength or temperature. Some time release formulations do not work properly if split, such as controlled-release tablet coatings, while other formulations such as micro-encapsulation still work if

8722-732: The side effects of opiate use like respiratory depression at high doses, constipation with chronic use, and addicting properties. Those with the following conditions should not be using opioids: The following are risk factors for opiate prescription abuse: Statistically, middle-aged patients with substance use history and psychiatric comorbidities are seen with higher mortality risks such as suicide. Iatrogenic 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. Modified-release dosage Modified-release dosage

8820-406: The swelling of skin and rashes. Tolerance to many of the effects of codeine, including its therapeutic effects, develops with prolonged use. This occurs at different rates for different effects, with tolerance to the constipation-inducing effects developing particularly slowly for instance. As with other opioids, a potentially serious adverse drug reaction is respiratory depression. This depression

8918-408: 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 . Oxymorphone is a congener of morphine. It is metabolized to 6-hydroxy-oxymorphone and oxymorphone-3-glucuronide, and 40% is excreted as metabolites. 6-hydroxy-oxymorphine is active and exists in a 1:1 ratio with

9016-571: The toxicity and death of neonates when codeine is administered to lactating mothers, particularly those with increased enzyme activity ("ultra-rapid" metabolizers). In 2019 Ireland was said to be on the verge of a codeine addiction epidemic, according to a paper in the Irish Medical Journal . Under Irish law, codeine can be bought over-the-counter under supervision of a pharmacist, but there is no mechanism to detect patients travelling to different pharmacies to purchase codeine. Codeine

9114-484: The use of codeine include drowsiness and constipation . Less common are itching , nausea , vomiting , dry mouth , miosis , orthostatic hypotension , urinary retention , euphoria , and dysphoria . Rare adverse effects include anaphylaxis , seizure , acute pancreatitis , and respiratory depression . As with all opiates, long-term effects can vary, but can include diminished libido, apathy, and memory loss. Some people may have allergic reactions to codeine, such as

9212-681: The use of osmotic pumps for oral drug delivery. Osmotic release systems have a number of major advantages over other controlled-release mechanisms. They are significantly less affected by factors such as pH , food intake, GI motility , and differing intestinal environments. Using an osmotic pump to deliver drugs has additional inherent advantages regarding control over drug delivery rates. This allows for much more precise drug delivery over an extended period of time, which results in much more predictable pharmacokinetics . However, osmotic release systems are relatively complicated, somewhat difficult to manufacture, and may cause irritation or even blockage of

9310-585: The various classes of morphine derivatives such as ketones, semisynthetics like dihydromorphine , halogeno-morphides, esters, ethers, and others have codeine, dihydrocodeine, and isocodeine analogues. The codeine ester acetylcodeine is a common active impurity in street heroin as some codeine tends to dissolve with the morphine when it is extracted from opium in underground heroin and morphine base labs. As an analgesic, codeine compares weakly to other opiates . Related to codeine in other ways are codoxime , thebacon , codeine- N -oxide (genocodeine), related to

9408-729: The world, codeine is, contingent on its concentration, a Schedule II and III drug under the Single Convention on Narcotic Drugs . In Australia , Canada , New Zealand , Sweden , the United Kingdom , the United States and many other countries, codeine is regulated under various narcotic control laws . In some countries, it is available without a medical prescription in combination preparations from licensed pharmacists in doses up to 20 mg, or 30 mg when sold combined with 500 mg paracetamol. As of 2015, of

9506-493: Was introduced as Codeonal in 1912, indicated for pain with nervousness. Codeine methylbromide is also considered a separate drug for various purposes. Codeine is the most widely used opiate in the world, and is one of the most commonly used drugs overall according to numerous reports by organizations including the World Health Organization and its League of Nations predecessor agency. It is often sold as

9604-470: Was upgraded to a black box warning in February 2013. Some patients are very effective converters of codeine to its active form, morphine, resulting in lethal blood levels. The FDA is presently recommending very cautious use of codeine in young tonsillectomy patients; the drug should be used in the lowest amount that can control the pain, "as needed" and not "around the clock", and immediate medical attention

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