What pill has a M with a Square around it and on the other side it says 05 then line then 52 on it?


Oxycodone HCL 5 mg has an M with a square and then says 05/52 on the other side. Its for pain relief.

More Info:

Key:BRUQQQPBMZOVGD-XFKAJCMBSA-NYes  Oxycodone is a semi-synthetic opioid synthesized from poppy-derived thebaine. It is a narcotic analgesic generally indicated for relief of moderate to severe pain. It was developed in 1916 in Germany as one of several new semi-synthetic opioids in an attempt to improve on the existing opioids. Oxycodone is available as single ingredient medication in immediate release and controlled release. Combination products formulated with non-narcotic ingredients such as NSAIDs and paracetamol are also available as immediate release formulation. Oxycodone has been in clinical use since 1917. and it is used for managing moderate to moderately severe acute or chronic pain. It has been found to improve quality of life for those with many types of pain. Controlled release oral tablet form is indicated for cancer and other chronic pains and intended to be taken every 12 hours. Immediate release forms are used more commonly for management of moderate pain. An Italian study concluded from investigating multiple studies that controlled release oxycodone is comparable to instant release oxycodone, morphine and hydromorphone in management of moderate to severe cancer pain. It indicated that side effect appears to be lesser than morphine and that it is a valid alternative to morphine and a first-line treatment for cancer pain. In 2001, the European Association for Palliative Care recommended that oral oxycodone could be taken as a second-line alternative to oral morphine for cancer pain. Oxycodone can be administered by parenteral or oral route. Starting dose of 5–15 mg oral every 4 to 6 hours or 10 mg controlled release every 12 hours. Maintenance dose of 10–30 mg every 4 hours or 20–640 mg controlled release form oxycodone per day for cancer pain with indication to use immediate release tablets as needed for break-through pain. Common side effects include constipation, fatigue, dizziness, nausea, vomiting, dry mouth, anxiety, itching, and sweating. Less common side effects (experienced by less than 5% of patients) include loss of appetite, nervousness, abdominal pain, diarrhea, urine retention, dyspnea, and hiccups, In high doses, overdoses, or in patients not tolerant to opiates, oxycodone can cause shallow breathing, bradycardia, cold-clammy skin, apnea, hypotension, miosis, circulatory collapse, respiratory arrest, and death. The risk of experiencing severe withdrawal symptoms is high if a patient has become physically dependent or addicted and discontinues oxycodone abruptly. Therefore, particularly in cases where the drug has been taken regularly over an extended period of time, use should be discontinued gradually rather than abruptly. People who use oxycodone in a recreational, hazardous, or harmful fashion (not as intended by the prescribing physician) are at even higher risk of severe withdrawal symptoms, as they tend to use higher-than-prescribed doses. The symptoms of oxycodone withdrawal are the same as for other opiate-based painkillers, and may include "anxiety, panic attack, nausea, insomnia, muscle pain, muscle weakness, fevers, and other flu-like symptoms". Withdrawal symptoms have also been reported in newborns whose mothers had been either injecting or orally taking oxycodone during pregnancy. Oxycodone and/or its major metabolites may be measured in blood or urine to monitor for clearance, abuse, confirm a diagnosis of poisoning, or assist in a medicolegal death investigation. Many commercial opiate screening tests cross-react appreciably with oxycodone and its metabolites, but chromatographic techniques can easily distinguish oxycodone from other opiates. In 1997, a group of Australian researchers proposed (based on a study in rats) that oxycodone acts on κ-opioid receptors, unlike morphine, which acts upon μ-opioid receptors. Further research by this group indicated the drug appears to be a κ2b-opioid agonist. However, this conclusion has been disputed, primarily on the basis that oxycodone produces effects that are typical of μ-opioid agonists, mainly because oxycodone is metabolized in the liver to oxymorphone as a metabolite, which is a more potent opioid agonist with stronger/higher binding affinity to μ-opioid receptors compared to oxycodone. In 2006, research by a Japanese group suggested the effect of oxycodone is mediated by different receptors in different situations. Specifically in diabetic mice, the κ-opioid receptor appears to be involved in the antinociceptive effects of oxycodone, while in nondiabetic mice, the μ1-opioid receptor seems to be primarily responsible for these effects. After a dose of conventional oral oxycodone, peak plasma levels of the drug are attained in about one hour; in contrast, after a dose of OxyContin (an oral controlled-release formulation), peak plasma levels of oxycodone occur in about three hours. Oxycodone in the blood is distributed to skeletal muscle, liver, intestinal tract, lungs, spleen, and brain. Conventional oral preparations start to reduce pain within 10–15 minutes on an empty stomach; in contrast, OxyContin starts to reduce pain within one hour. Oxycodone is metabolized to α and β oxycodol; oxymorphone, then α and β oxymorphol and noroxymorphone; and noroxycodone, then α and β noroxycodol and noroxymorphone (N-desmethyloxycodone). (14-Hydroxydihydrocodeine that in turn becomes 14-Hydroxydihydromorphine) These metabolites are true only for humans. As many as six metabolites for oxycodone (14-hydroxydihydromorphinone, 14-hydroxydihydrocodeine, 14-hydroxydihydrocodeinone N-oxide {oxycodone N-oxide}, 14-hydroxydihydroisocodeine, 14-hydroxydihydrocodeine N-oxide, and noroxycodone) have been found in rabbits, several of which are thought to be active metabolites to some extent, although a study using conventional oral oxycodone concluded oxycodone itself, and not its metabolites, is predominantly responsible for the drug's opioid effects on the brain. Oxycodone is metabolized by the cytochrome P450 enzyme system in the liver, making it vulnerable to drug interactions. Some people are fast metabolizers, resulting in reduced analgesic effect, but increased adverse effects, while others are slow metabolisers, resulting in increased toxicity without improved analgesia. The dose of OxyContin must be reduced in patients with reduced hepatic function. Oxycodone and its metabolites are mainly excreted in the urine and sweat; therefore, it accumulates in patients with renal impairment. Oxycodone can be administered orally, intranasally, via intravenous, intramuscular, or subcutaneous injection, or rectally. The bioavailability of oral administration of oxycodone averages 60–87%, with rectal administration yielding the same results; intranasal varies between individuals with a mean of 46%. Taken orally, the conversion ratio between morphine to extended release oxycodone is reported as 2:1 Oxycodone's chemical name is derived from codeine. The chemical structures are very similar, differing only in that It is also similar to hydrocodone, differing only in that it has a hydroxyl group at carbon-14. Expanded expression for the compound oxycodone in the academic literature include "dihydrohydroxycodeinone", "Eucodal", "Eukodal", "14-hydroxydihydrocodeinone", and "Nucodan". In a UNESCO convention, the translations of "oxycodone" are oxycodon (Dutch), oxycodone (French), oxicodona (Spanish), الأوكسيكودون (Arabic), 羟考酮 (Chinese), and оксикодон (Russian). The word "oxycodone" should not be confused with "oxandrolone", "oxazepam", "oxybutynin", "oxytocin", or "Roxanol". Freund and Speyer of the University of Frankfurt in Germany first synthesized oxycodone from thebaine in 1916, a few years after the German pharmaceutical company Bayer had stopped the mass production of heroin due to hazardous use, harmful use, and dependence. It was hoped that a thebaine-derived drug would retain the analgesic effects of morphine and heroin with less dependence. To some extent this was achieved, as oxycodone does not have the same immediate effect as heroin or morphine, nor does it last as long.][ The first clinical use of the drug was documented in 1917, the year after it was first developed. It was first introduced to the US market in May 1939. In early 1928, Merck introduced a combination product containing scopolamine, oxycodone, and ephedrine under the German initials for the ingredients SEE, which was later renamed Scophedal (SCOpolamine ePHEDrine and eukodAL)—this combination is essentially an oxycodone analogue of the morphine-based Twilight Sleep with ephedrine added to reduce circulatory and respiratory effects. As of May 2013, extended release version in the United States is only available as OxyContin brand. The International Narcotics Control Board estimated 11.5 tons (23,000 lbs) of oxycodone were manufactured worldwide in 1998; by 2007, this figure had grown to 75.2 tons (150,400 lbs). United States accounted for 82% of consumption in 2007 at 51.6 tons. Canada, Germany, Australia and France combined accounted for 13% of consumption in 2007. pp. 92 In August 2010, Purdue Pharma reformulated their OxyContin product line to use an abuse-resistant polymer designed to decrease abuse potential by defeating the release mechanism. The FDA approved relabeling the reformulated version as abuse-resistant in April 2013. The non-medical use of OxyContin began in Australia in the early 2000s. By 2007, 51% of a national sample of injection drug users in Australia had reported using oxycodone, and 27% had injected it in the last six months. Deaths from opioid pain relievers increased from 13.7 deaths per million residents in 1991 to 27.2 deaths per million residents in 2004.] [ The abuse of oxycodone in Canada became a problem. Areas where oxycodone is most problematic are Atlantic Canada and Ontario, where its abuse is prevalent in rural towns, and in many smaller to medium-sized cities. Oxycodone is also widely available across Western Canada, but methamphetamine and heroin are more serious problems in the larger cities, while oxycodone is more common in rural towns. Oxycodone is diverted through doctor shopping, prescription forgery, pharmacy theft, and overprescribing. Abuse and diversion of oxycodone in the UK commenced in the early- to mid-2000s. The first known death due to overdose in the UK occurred in 2002. However, recreational use remains relatively rare. Oxycodone is subject to international conventions on narcotic drugs. In addition, oxycodone is subject to national laws that differ by country. The 1931 Convention for Limiting the Manufacture and Regulating the Distribution of Narcotic Drugs of the League of Nations included oxycodone. The 1961 Single Convention on Narcotic Drugs of the United Nations, which replaced the 1931 convention, categorized oxycodone in Schedule I. Global restrictions on Schedule I drugs include "limit[ing] exclusively to medical and scientific purposes the production, manufacture, export, import, distribution of, trade in, use and possession of" these drugs; "requir[ing] medical prescriptions for the supply or dispensation of [these] drugs to individuals"; and "prevent[ing] the accumulation" of quantities of these drugs "in excess of those required for the normal conduct of business". Oxycodone is in Schedule I (derived from the Single Convention on Narcotic Drugs) of the Commonwealth's Narcotic Drugs Act 1967. In addition, it is in Schedule 8 of the Australian Standard for the Uniform Scheduling of Drugs and Poisons ("Poisons Standard"), meaning it is a "controlled drug... which should be available for use but require[s] restriction of manufacture, supply, distribution, possession and use to reduce abuse, misuse and physical or psychological dependence". Oxycodone is a controlled substance under Schedule I of the Controlled Drugs and Substances Act (CDSA). In February 2012, Ontario passed legislation to allow the expansion of an already existing drug-tracking system for publicly funded drugs to include those that are privately insured. This database will function to identify and monitor patient’s attempts to seek prescriptions from multiple doctors or retrieve from multiple pharmacies. Other provinces have proposed similar legislation, while some, such as Nova Scotia, have legislation already in effect for monitoring prescription drug use. These changes have coincided with other changes in Ontario’s legislation to target the misuse of painkillers and high addiction rates to drugs such as oxycodone. As of February 29, 2012, Ontario passed legislation delisting oxycodone from the province’s public drug benefit program. This was a first for any province to delist a drug based on addictive properties. The new law prohibits prescriptions for OxyNeo except to certain patients under the Exceptional Access Program including palliative care and in other extenuating circumstances. Patients already prescribed oxycodone will receive coverage for an additional year for OxyNeo, and after that, it will be disallowed unless designated under the exceptional access program. Much of the legislative activity has stemmed from Purdue Pharma’s decision in 2011 to begin a modification of oxycodone’s composition to make it more difficult to crush for snorting or injecting. The new formulation, OxyNeo, is intended to be preventative in this regard and retain its effectiveness as a pain killer. Since introducing its Narcotics Safety and Awareness Act, Ontario has committed to focusing on drug addiction, particularly in the monitoring and identification of problem opioid prescriptions, as well as the education of patients, doctors, and pharmacists. This Act, introduced in 2010, commits to the establishment of a unified database to fulfill this intention. Both the public and medical community have received the legislation positively, though concerns about the ramifications of legal changes have been expressed. Because laws are largely provincially regulated, many speculate a national strategy is needed to prevent smuggling across provincial borders from jurisdictions with looser restrictions. Several class action suits across Canada have been launched against the Purdue group of companies and affiliates. Claimants argue the pharmaceutical manufacturers did not meet a standard of care and were negligent in doing so. These lawsuits reference earlier judgments in the United States, which held that Purdue was liable for wrongful marketing practices and misbranding. Since 2007, the Purdue companies have paid over $650 million in settling litigation or facing criminal fines. The drug is in Appendix III of the Narcotics Act (Betäubungsmittelgesetz or BtMG). The law allows only physicians, dentists, and veterinarians (Ärzte, Zahnärzte und Tierärzte) can prescribe oxycodone, and the federal government can regulate the prescriptions (e.g., by requiring reporting). Oxycodone is regulated under Part I of Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance. Oxycodone is listed as a Class A drug in the Misuse of Drugs Act of Singapore, which means offences in relation to the drug attract the most severe level of punishment. A conviction for unauthorized manufacture of the drug attracts a minimum sentence of 10 years of imprisonment and corporal punishment of five strokes of the cane, and a maximum sentence of life imprisonment or 30 years of imprisonment and 15 strokes of the cane. The minimum and maximum penalties for unauthorized trafficking in the drug are respectively five years of imprisonment and five strokes of the cane, and 20 years of imprisonment and 15 strokes of the cane. Oxycodone is a Class A drug under the Misuse of Drugs Act. For Class A drugs, which are "considered to be the most likely to cause harm", possession without a prescription is punishable by up to seven years in prison, an unlimited fine, or both. Dealing of the drug illegally is punishable by up to life imprisonment, an unlimited fine, or both. In addition, oxycodone is a Schedule 2 drug per the Misuse of Drugs Regulations 2001 which "provide certain exemptions from the provisions of the Misuse of Drugs Act 1971". Oxycodone is a Schedule II controlled substance
M: CNS anat (n/s/m/p/4/e/b/d/c/a/f/l/g)/phys/devp noco (m/d/e/h/v/s)/cong/tumr, sysi/epon, injr proc, drug (N1A/2AB/C/3/4/7A/B/C/D)

Key:LLPOLZWFYMWNKH-CMKMFDCUSA-NYes  Hydrocodone is a semi-synthetic opioid derived from codeine. Hydrocodone is used orally as narcotic analgesic and antitussive, often in combination with paracetamol (acetaminophen) or ibuprofen. Hydrocodone is prescribed predominantly in the United States. International Narcotics Control Board reports that 99% of worldwide supply in 2007 was consumed in the United States. Hydrocodone is used to treat moderate to severe pain and as an antitussive to treat cough. It is approximately 1.5 times less potent opioid than oxycodone. Analgesic action of hydrocodone begins 20–30 minutes after taking it and lasts 4–8 hours. Common side effects of hydrocodone are nausea, vomiting, constipation, drowsiness, dizziness, lightheadedness, fuzzy thinking, anxiety, abnormally happy or sad mood, dry throat, difficulty urinating, rash, itching, and narrowing of the pupils. Serious side effects include slowed or irregular breathing and chest tightness. Several cases of progressive bilateral hearing loss unresponsive to steroid therapy have been described as an infrequent adverse reaction to hydrocodone/acetaminophene abuse. This adverse effect has been considered due to the ototoxicity of hydrocodone. Recently, researchers suggested that acetaminophen is the primary agent responsible for the ototoxicity. It is in FDA pregnancy category C. No adequate and well-controlled studies in humans have been conducted. A newborn of a mother taking opioid medications regularly prior to the birth will be physically dependent. The baby may also exhibit respiratory depression if the opioid dose was high. An epidemiological study indicated that opioid treatment during early pregnancy results in increased risk of various birth defects. Symptoms of hydrocodone overdose include narrowed or widened pupils; slow, shallow, or stopped breathing; slowed or stopped heartbeat; cold, clammy, or blue skin; excessive sleepiness; loss of consciousness; seizures; and death. Hydrocodone can be habit-forming, causing physical and psychological dependence. Its abuse liability is similar to morphine and less than oxycodone. Patients consuming alcohol, other opioids, antihistamines, antipsychotics, antianxiety agents, or other central nervous system (CNS) depressants together with hydrocodone may exhibit an additive CNS depression. Hydrocodone may interact with serotonergic medications. As a narcotic, hydrocodone relieves pain by binding to opioid receptors in the CNS. It acts primarily on μ-opioid receptors, with about six times lesser affinity to δ-opioid receptors. In blood, 20-50% of hydrocodone is bound to protein. Studies have shown hydrocodone is stronger than codeine but only one-tenth as potent as morphine at binding to receptors and reported to be only 59% as potent as morphine in analgesic properties. However, in tests conducted on rhesus monkeys, the analgesic potency of hydrocodone was actually higher than morphine. Per os hydrocodone has a mean equivalent daily dosage (MEDD) factor of .4, meaning that 1 mg of hydrocodone is equivalent to .4 mg of intravenous morphine. However, because of morphine's low oral bioavailability, there is a 1:1 correspondence between orally administered morphine and orally administered hydrocodone. Hydrocodone is biotransformed by the liver into several metabolites, and has a serum half-life that averages 3.8 hours. The hepatic cytochrome P450 enzyme CYP2D6 converts it into hydromorphone, a more potent opioid. However, extensive and poor cytochrome 450 CYP2D6 metabolizers had similar physiological and subjective responses to hydrocodone, and CYP2D6 inhibitor quinidine did not change the responses of extensive metabolizers, suggesting that inhibition of CYP2D6 metabolism of hydrocodone has no practical importance. Ultrarapid CYP2D6 metabolizers (1-2% of the population) may have an increased response to hydrocodone; however, hydrocodone metabolism in this population has not been studied. A major metabolite, norhydrocodone, is predominantly formed by CYP3A4-catalyzed oxidation. Inhibition of CYP3A4 in a child who was, in addition, a poor CYP2D6 metabolizer, resulted in a fatal overdose of hydrocodone. Approximately 40% of hydrocodone metabolism is attributed to non-cytochrome catalyzed reactions. Commercial hydrocodone preparations are always combined with another medication. The rationale of combining hydrocodone with other pain-killers is that the combination may increase efficacy, and the adverse effects may be reduced as compared with an equally effective dose of a single agent. A combination of hydrocodone and ibuprofen was more effective than either of the drugs on their own in relieving postoperative pain. The overall effect of the combination could be presented as a sum of the effects of ibuprofen and hydrocodone, which is consistent with differing mechanisms of action of these drugs. Similar results were observed for hydrocodone-acetaminophen combination. Four pharmaceutical companies (Purdue Pharma, Cephalon, Zogenix, and Egalet) are developing extended-release formulations of hydrocodone by itself. These formulations are expected to avoid the issue of hepatotoxicity of acetaminophen containing formulations. They may also have lower abuse potential. Many users of hydrocodone report a sense of satisfaction, especially at higher doses. A number of users also report a warm or pleasant numbing sensation throughout the body, one of the best known effects of narcotics.][ Withdrawal symptoms may include, but are not limited to; severe pain, pins and needles sensation throughout body, sweating, extreme anxiety and restlessness, sneezing, watery eyes, fever, depression, stomach cramps, diarrhea, and extreme drug cravings, among others.][ Taking over 4,000 milligrams (4 grams) of paracetamol in a period of 24 hours can result in paracetamol overdose and severe hepatotoxicity; doses in the range of 15,000–20,000 milligrams a day have been reported as fatal. Taking hydrocodone with grapefruit juice is one of the measures believed to enhance its narcotic effect. It is believed that CYP3A4 inhibitors in grapefruit juice may decrease metabolism of hydrocodone, although there has been no research into this issue. Hydrocodone may be quantitated in blood, plasma or urine to monitor for misuse, confirm a diagnosis of poisoning or assist in a medicolegal death investigation. Many commercial opiate screening tests cross-react appreciably with hydrocodone and its metabolites, but chromatographic techniques can easily distinguish hydrocodone from other opiates. Blood or plasma hydrocodone concentrations are typically in the 5-30 µg/L range in persons taking the drug therapeutically, 100-200 µg/L in abusers and 0.1-1.6 mg/L in cases of acute fatal overdosage. In Australia, hydrocodone is a Schedule 8 (S8) or Controlled Drug. Hydrocodone is regulated in the same fashion as in Germany (see below) under the Austrian Suchtmittelgesetz; since 2002 it has been available in the form of German products and those produced elsewhere in the European Union under Article 76 of the Schengen Treaty—prior to this, no Austrian companies produced hydrocodone products, with dihydrocodeine and nicomorphine being more commonly used for the same levels of pain and the former for coughing. In Belgium, hydrocodone is no longer available for medical use. In France, hydrocodone (Vicodin) is no longer available for medical use. Hydrocodone is a prohibited narcotic. In Germany, hydrocodone is no longer available for medical use. Hydrocodone is listed under the Betäubungsmittelgesetz as a Suchtgift in the same category as morphine. In Luxembourg, hydrocodone is available by prescription under the name Biocodone. Prescriptions are more commonly given for use as a cough suppressant (antitussive) rather than for pain relief (analgesic). In the Netherlands, hydrocodone is not available for medical use and is classified as a List 1 drug under the Opium Law. Hydrocodone is no longer available for medical use. The last remaining formula was banned in 1967. In the UK, hydrocodone is not available for medical use and is listed as a Class A drug under the Misuse of Drugs Act 1971. Various formulations of dihydrocodeine, a weaker opioid, are frequently used as an alternative for the aforementioned indications of hydrocodone use. In the U.S., formulations containing more than 15 mg per dosage unit are considered Schedule II drugs, as would any formulation consisting of just hydrocodone alone. Those containing less than or equal to 15 mg per dosage unit in combination with acetaminophen or another non-controlled drug are called hydrocodone compounds and are considered Schedule III drugs. Hydrocodone is typically found in combination with other drugs such as acetaminophen, aspirin, ibuprofen and homatropine methylbromide. The purpose of the non-controlled drugs in combination is often twofold: 1) To provide increased analgesia via drug synergy. 2) To limit the intake of hydrocodone by causing unpleasant and often unsafe side effects at higher-than-prescribed doses. Hydrocodone is not commercially available in pure form in the United States due to a separate regulation, and is always sold with an NSAID, paracetamol, antihistamine, expectorant, or homatropine. Pure hydrocodone is a more strictly controlled Schedule II drug and sold by compounding pharmacies. The cough preparation Codiclear DH is the purest commercial US hydrocodone item, containing guaifenesin and small amounts of ethanol as active ingredients. Under the Controlled Substances Act (CSA), hydrocodone is listed as both a Schedule II and Schedule III substance depending on the formulation. Hydrocodone was until recently the active antitussive in more than 200 formulations of cough syrups and tablets sold in the United States. In late 2006, the FDA began forcing the recall of many of these formulations due to reports of deaths in infants and children under the age of six. The legal status of drug formulations originally sold between 1938 and 1962—before FDA approval was required—was ambiguous. As a result of FDA enforcement action, by August 2010, 88% of the hydrocodone-containing medications had been removed from the market.][ At the present time][, doctors, pharmacists, and codeine-sensitive or allergic patients or sensitive to the amounts of histamine released by its metabolites must choose among rapidly dwindling supplies of the Hycodan-Codiclear-Hydromet type syrups, Tussionex—an extended-release suspension similar to the European products Codipertussin (codeine hydrochloride), Paracodin suspension (dihydrocodeine hydroiodide), Tusscodin (nicocodeine hydrochloride) and others—and a handful of weak dihydrocodeine syrups. The low sales volume and Schedule II status of Dilaudid cough syrup predictably leads to under-utilisation of the drug. There are several conflicting views concerning the US availability of cough preparations containing ethylmorphine (also called dionine or codethyline)—Feco Syrup and its equivalents were first marketed circa 1895 and still in common use in the 1940s and 1950s, and the main ingredient is treated like codeine under the Controlled Substances Act of 1970.][ In the U.S., hydrocodone is always found in combination with other drugs such as paracetamol (also called acetaminophen), aspirin, an NSAID, ibuprofen, an antihistamine, an expectorant, or homatropine methylbromide due to compounding regulations. These combinations are considered C-III substances, prescriptions for which are generally valid for 6 months, including refills. The purpose of the non-controlled drugs in combination is often twofold: The cough preparation Codiclear DH is the purest US hydrocodone item, containing guaifenesin and small amounts of ethanol as active ingredients.][ As of July 2010, the FDA was considering banning some hydrocodone and oxycodone fixed-combination proprietary prescription drugs—based on the paracetamol content and the widespread occurrence of liver problems. FDA action on this suggestion would ostensibly also affect codeine and dihydrocodeine products such as the Tylenol With Codeine and Panlor series of drugs.][ In 2010, it was the most prescribed drug in the USA, with 131.2 million prescriptions of hydrocodone (combined with paracetamol) being written. Hydrocodone was first synthesized in Germany in 1920 by Carl Mannich and Helene Löwenheim. It was approved by the Food and Drug Administration on 23 March 1943 for sale in the United States and approved by Health Canada for sale in Canada under the brand name Hycodan. M: CNS anat (n/s/m/p/4/e/b/d/c/a/f/l/g)/phys/devp noco (m/d/e/h/v/s)/cong/tumr, sysi/epon, injr proc, drug (N1A/2AB/C/3/4/7A/B/C/D) M: RES anat (n, x, l, c)/phys/devp noco (c, p)/cong/tumr, sysi/epon, injr proc, drug (R1/2/3/5/6/7)

Key:BQJCRHHNABKAKU-KBQPJGBKSA-NYes  Morphine (INN) (; MS Contin, MSIR, Avinza, Kadian, Oramorph, Roxanol, Kapanol) is a potent opiate analgesic drug that is used to relieve severe pain. It was first isolated in 1804 by Friedrich Sertürner, which is generally believed to be the first ever isolation of a natural plant alkaloid in history. It was first distributed by him in 1817; and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more widely used after the invention of the hypodermic needle in 1857. Sertürner originally named the substance morphium after the Greek god of dreams Morpheus (Greek: ) for its tendency to cause sleep. After it was isolated from opium by Sertürner, the traditional way to obtain morphine had been by chemical processing of opium. In India, opium harvested by licensed poppy farmers is dehydrated to uniform levels of hydration at government processing centers, and then sold to pharmaceutical companies, which extract morphine from the opium. However in Turkey and Tasmania morphine is obtained by harvesting and processing the fully mature dry seed pods, with attached stalks, called poppy straw. By not harvesting opium at all, and by obtaining morphine only from the dry poppy straw, and not from opium, and by using a large scale industrial process to do so, at factories located near the poppy farms, opportunities for illicitly diverting opium from the crop, and for illicit production of morphine, and heroin from the opium, are reduced. In Turkey, a water extraction process is used. In Tasmania, a solvent extraction process is used. Morphine is the most abundant opiate found in opium, the dried latex extracted by shallowly slicing the unripe seedpods of the Papaver somniferum poppy. Morphine was the first active principle purified from a plant source and is one of at least 50 alkaloids of several different types present in opium, poppy straw concentrate, and other poppy derivatives. Morphine is generally 8 to 14 percent of the dry weight of opium, although specially bred cultivars reach 26 percent or produce little morphine at all (under 1 percent, perhaps down to 0.04 percent). The latter varieties, including the 'Przemko' and 'Norman' cultivars of the opium poppy, are used to produce two other alkaloids, thebaine and oripavine, which are used in the manufacture of semi-synthetic and synthetic opioids like oxycodone and etorphine and some other types of drugs. P. bracteatum does not contain morphine or codeine, or other narcotic phenanthrene-type, alkaloids. This species is rather a source of thebaine. Occurrence of morphine in other Papaverales and Papaveraceae, as well as in some species of hops and mulberry trees has not been confirmed. Morphine is produced most predominantly early in the life cycle of the plant. Past the optimum point for extraction, various processes in the plant produce codeine, thebaine, and in some cases negligible amounts of hydromorphone, dihydromorphine, dihydrocodeine, tetrahydro-thebaine, and hydrocodone (these compounds are rather synthesized from thebaine and oripavine). The human body produces endorphins, which are endogenous opioid peptides that function as neurotransmitters and have similar effects. In clinical medicine, morphine is regarded as the gold standard, or benchmark, of opioid analgesics used to relieve severe or agonizing pain and suffering. Like other opioids, such as oxycodone, hydromorphone, and diacetylmorphine (heroin), morphine acts directly on the central nervous system (CNS) to relieve pain. Morphine has a high potential for addiction; tolerance and psychological dependence develop rapidly, although physiological dependence may take several months to develop. Tolerance to respiratory depression and euphoria develops more rapidly than tolerance to analgesia, and many chronic pain patients are being maintained on a stable dose, for many years. Morphine is primarily used to treat both acute and chronic severe pain. It is also used for pain due to myocardial infarction and for labor pains. There are however concerns that morphine may increase mortality in the setting of non ST elevation myocardial infarction. Morphine has also traditionally been used in the treatment of the acute pulmonary edema. A 2006 review however found little evidence to support this practice. Immediate release morphine is beneficial in reducing the symptom of acute shortness of breath due to both cancer and non-cancer causes. In the setting of breathlessness at rest or on minimal exertion from conditions such as advanced cancer or end-stage cardio-respiratory diseases, regular, low-dose sustained release morphine significantly reduces breathlessness safely, with its benefits maintained over time. Its duration of analgesia is about 3–4 hours when administered via the intravenous, subcutaneous, or intramuscular route and 3–6 hours when given by mouth. Morphine is also used in slow release formulations for opiate substitution therapy (OST) in Austria, Bulgaria, and Slovenia, for addicts who cannot tolerate the side effects of using either methadone or buprenorphine, or for addicts who are "not held" by buprenorphine or methadone. It is used for OST in many parts of Europe although on a limited basis. Like loperamide and other opioids, morphine acts on the myenteric plexus in the intestinal tract, reducing gut motility, causing constipation. The gastrointestinal effects of morphine are mediated primarily by μ-opioid receptors in the bowel. By inhibiting gastric emptying and reducing propulsive peristalsis of the intestine, morphine decreases the rate of intestinal transit. Reduction in gut secretion and increased intestinal fluid absorption also contribute to the constipating effect. Opioids also may act on the gut indirectly through tonic gut spasms after inhibition of nitric oxide generation. This effect was shown in animals when a nitric oxide precursor, L-Arginine, reversed morphine-induced changes in gut motility. Morphine is a potentially highly addictive substance. It can cause psychological dependence and physical dependence as well as tolerance. In the presence of pain and the other disorders for which morphine is indicated, a combination of psychological and physiological factors tend to prevent true addiction from developing, although physical dependence and tolerance will develop with protracted opioid therapy. In controlled studies comparing the physiological and subjective effects of heroin and morphine in individuals formerly addicted to opiates, subjects showed no preference for one drug over the other. Equipotent, injected doses had comparable action courses, with no difference in subjects' self-rated feelings of euphoria, ambition, nervousness, relaxation, drowsiness, or sleepiness. Short-term addiction studies by the same researchers demonstrated that tolerance developed at a similar rate to both heroin and morphine. When compared to the opioids hydromorphone, fentanyl, oxycodone, and pethidine/meperidine, former addicts showed a strong preference for heroin and morphine, suggesting that heroin and morphine are particularly susceptible to abuse and addiction. Morphine and heroin were also much more likely to produce euphoria and other positive subjective effects when compared to these other opioids. The choice of heroin and morphine over other opioids by former-drug addicts may also be the result of the fact that heroin (also known as morphine diacetate, diamorphine or di-acetyl-morphine) is an ester of morphine and a morphine prodrug, essentially meaning that they are identical drugs in vivo. Heroin is converted to morphine before binding to the opioid receptors in the brain and spinal cord, where morphine then causes the subjective effects, which is what the addicted individuals are ultimately looking for. Other studies, such as the Rat Park experiments, suggest that morphine is less physically addictive than others suggest, and most studies on morphine addiction merely show that "severely distressed animals, like severely distressed people, will relieve their distress pharmacologically if they can." In these studies, rats with a morphine "addiction" overcome their addiction themselves when placed in decent living environments with enough space, good food, companionship, areas for exercise, and areas for privacy. More recent research has shown that an enriched environment may decrease morphine addiction in mice. Tolerance to the analgesic effects of morphine is fairly rapid][. There are several hypotheses about how tolerance develops, including opioid receptor phosphorylation (which would change the receptor conformation), functional decoupling of receptors from G-proteins (leading to receptor desensitization), μ-opioid receptor internalization and/or receptor down-regulation (reducing the number of available receptors for morphine to act on), and upregulation of the cAMP pathway (a counterregulatory mechanism to opioid effects) (For a review of these processes, see Koch and Hollt.) CCK might mediate some counter-regulatory pathways responsible for opioid tolerance. CCK-antagonist drugs, specifically proglumide, have been shown to slow the development of tolerance to morphine. Cessation of dosing with morphine creates the prototypical opioid withdrawal syndrome, which, unlike that of barbiturates, benzodiazepines, alcohol, or sedative-hypnotics, is not fatal by itself in neurologically healthy patients without heart or lung problems. Acute morphine along with and other opioid withdrawal proceeds through a number of stages. Other opioids differ in the intensity and length of each, and weak opioids and mixed agonist-antagonists may have acute withdrawal syndromes that do not reach the highest level. As commonly cited][, they are: The withdrawal symptoms associated with morphine addiction are usually experienced shortly before the time of the next scheduled dose, sometimes within as early as a few hours (usually between 6–12 hours) after the last administration. Early symptoms include watery eyes, insomnia, diarrhea, runny nose, yawning, dysphoria, sweating and in some cases a strong drug craving. Severe headache, restlessness, irritability, loss of appetite, body aches, severe abdominal pain, nausea and vomiting, tremors, and even stronger and more intense drug craving appear as the ome progresses. Severe depression and vomiting are very common. During the acute withdrawal period systolic and diastolic blood pressure increase, usually beyond pre-morphine levels, and heart rate increases, which have potential to cause a heart attack, blood clot, or stroke. Chills or cold flashes with goose bumps ("cold turkey") alternating with flushing (hot flashes), kicking movements of the legs ("kicking the habit") and excessive sweating are also characteristic symptoms. Severe pains in the bones and muscles of the back and extremities occur, as do muscle spasms. At any point during this process, a suitable narcotic can be administered that will dramatically reverse the withdrawal symptoms. Major withdrawal symptoms peak between 48 and 96 hours after the last dose and subside after about 8 to 12 days. Sudden withdrawal by heavily dependent users who are in poor health is very rarely fatal. Morphine withdrawal is considered less dangerous than alcohol, barbiturate, or benzodiazepine withdrawal. The psychological dependence associated with morphine addiction is complex and protracted. Long after the physical need for morphine has passed, the addict will usually continue to think and talk about the use of morphine (or other drugs) and feel strange or overwhelmed coping with daily activities without being under the influence of morphine. Psychological withdrawal from morphine is a very long and painful process. Addicts often suffer severe depression, anxiety, insomnia, mood swings, amnesia (forgetfulness), low self-esteem, confusion, paranoia, and other psychological disorders. Without intervention, the syndrome will run its course, and most of the overt physical symptoms will disappear within 7 to 10 days including psychological dependence. There is a high probability that relapse will occur after morphine withdrawal when neither the physical environment nor the behavioral motivators that contributed to the abuse have been altered. Testimony to morphine's addictive and reinforcing nature is its relapse rate. Abusers of morphine (and heroin) have one of the highest relapse rates among all drug users, ranging up to 98 per cent in the estimation of some clinicians, neuropharmacologists, mental health/AODA professionals and other medical experts. A large overdose can cause asphyxia and death by respiratory depression if the person does not receive medical attention immediately. Overdose treatment includes the administration of naloxone. The latter completely reverses morphine's effects, but precipitates immediate onset of withdrawal in opiate-addicted subjects. Multiple doses may be needed. The minimum lethal dose is 200 mg but in case of hypersensitivity 60 mg can bring sudden death. In case of drug addiction, 2–3 g/day can be tolerated. The following conditions are relative contraindications for morphine: Although it has previously been thought that morphine was contraindicated in acute pancreatitis, a review of the literature shows no evidence for this. The first synthesis by Marshall D. Gates, Jr. in 1952 is considered a classic in the field. Several other syntheses were reported, notably by the research groups of Rice, Evans, Fuchs, Parker, Overman, Mulzer-Trauner, White, Taber, Trost, Fukuyama, Guillou and Stork. Endogenous opioids include endorphins, enkephalins, dynorphins, and even morphine itself. Morphine appears to mimic endorphins. Endorphins, a contraction of the term endogenous morphines, are responsible for analgesia (reducing pain), causing sleepiness, and feelings of pleasure. They can be released in response to pain, strenuous exercise, orgasm, or excitement. Morphine is the prototype narcotic drug and is the standard against which all other opioids are tested. It interacts predominantly with the μ-opioid receptor. These μ-binding sites are discretely distributed in the human brain, with high densities in the posterior amygdala, hypothalamus, thalamus, nucleus caudatus, putamen, and certain cortical areas. They are also found on the terminal axons of primary afferents within laminae I and II (substantia gelatinosa) of the spinal cord and in the spinal nucleus of the trigeminal nerve. Morphine is a phenanthrene opioid receptor agonist – its main effect is binding to and activating the μ-opioid receptors in the central nervous system. In clinical settings, morphine exerts its principal pharmacological effect on the central nervous system and gastrointestinal tract. Its primary actions of therapeutic value are analgesia and sedation. Activation of the μ-opioid receptors is associated with analgesia, sedation, euphoria, physical dependence, and respiratory depression. Morphine is a rapid-acting narcotic, and it is known to bind very strongly to the μ-opioid receptors, and for this reason, it often has a higher incidence of euphoria/dysphoria, respiratory depression, sedation, pruritus, tolerance, and physical and psychological dependence when compared to other opioids at equianalgesic doses. Morphine is also a κ-opioid and δ-opioid receptor agonist, κ-opioid's action is associated with spinal analgesia, miosis (pinpoint pupils) and psychotomimetic effects. δ-opioid is thought to play a role in analgesia. Although morphine does not bind to the σ-receptor, it has been shown that σ-agonists, such as (+)-pentazocine, antagonize morphine analgesia, and σ-antagonists enhance morphine analgesia, suggesting some interaction between morphine and the σ-opioid receptor. The effects of morphine can be countered with opioid antagonists such as naloxone and naltrexone; the development of tolerance to morphine may be inhibited by NMDA antagonists such as ketamine or dextromethorphan. The rotation of morphine with chemically dissimilar opioids in the long-term treatment of pain will slow down the growth of tolerance in the longer run, particularly agents known to have significantly incomplete cross-tolerance with morphine such as levorphanol, ketobemidone, piritramide, and methadone and its derivatives; all of these drugs also have NMDA antagonist properties. It is believed that the strong opioid with the most incomplete cross-tolerance with morphine is either methadone or dextromoramide. Studies have shown that morphine can alter the expression of a number of genes. A single injection of morphine has been shown to alter the expression of two major groups of genes, for proteins involved in mitochondrial respiration and for cytoskeleton-related proteins. Morphine has long been known to act on receptors expressed on cells of the central nervous system resulting in pain relief and analgesia. In the 1970s and '80s, evidence suggesting that opiate drug addicts show increased risk of infection (such as increased pneumonia, tuberculosis, and HIV) led scientists to believe that morphine may also affect the immune system. This possibility increased interest in the effect of chronic morphine use on the immune system. The first step of determining that morphine may affect the immune system was to establish that the opiate receptors known to be expressed on cells of the central nervous system are also expressed on cells of the immune system. One study successfully showed that dendritic cells, part of the innate immune system, display opiate receptors. Dendritic cells are responsible for producing cytokines, which are the tools for communication in the immune system. This same study showed that dendritic cells chronically treated with morphine during their differentiation produce more interleukin-12 (IL-12), a cytokine responsible for promoting the proliferation, growth, and differentiation of T-cells (another cell of the adaptive immune system) and less interleukin-10 (IL-10), a cytokine responsible for promoting a B-cell immune response (B cells produce antibodies to fight off infection). This regulation of cytokines appear to occur via the p38 MAPKs (mitogen-activated protein kinase)-dependent pathway. Usually, the p38 within the dendritic cell expresses TLR 4 (toll-like receptor 4), which is activated through the ligand LPS (lipopolysaccharide). This causes the p38 MAPK to be phosphorylated. This phosphorylation activates the p38 MAPK to begin producing IL-10 and IL-12. When the dendritic cells are chronically exposed to morphine during their differentiation process then treated with LPS, the production of cytokines is different. Once treated with morphine, the p38 MAPK does not produce IL-10, instead favoring production of IL-12. The exact mechanism through which the production of one cytokine is increased in favor over another is not known. Most likely, the morphine causes increased phosphorylation of the p38 MAPK. Transcriptional level interactions between IL-10 and IL-12 may further increase the production of IL-12 once IL-10 is not being produced. This increased production of IL-12 causes increased T-cell immune response. Further studies on the effects of morphine on the immune system have shown that morphine influences the production of neutrophils and other cytokines. Since cytokines are produced as part of the immediate immunological response (inflammation), it has been suggested that they may also influence pain. In this way, cytokines may be a logical target for analgesic development. Recently, one study has used an animal model (hind-paw incision) to observe the effects of morphine administration on the acute immunological response. Following hind-paw incision, pain thresholds and cytokine production were measured. Normally, cytokine production in and around the wounded area increases in order to fight infection and control healing (and, possibly, to control pain), but pre-incisional morphine administration (0.1-10.0 mg/kg) reduced the number of cytokines found around the wound in a dose-dependent manner. The authors suggest that morphine administration in the acute post-injury period may reduce resistance to infection and may impair the healing of the wound. Morphine can be taken orally, sublingually, bucally, rectally, subcutaneously, intravenously, intrathecally or epidurally and inhaled via a nebulizer. On the streets, it is becoming more common to inhale (“Chasing the Dragon"), but, for medical purposes, intravenous (IV) injection is the most common method of administration. Morphine is subject to extensive first-pass metabolism (a large proportion is broken down in the liver), so, if taken orally, only 40–50% of the dose reaches the central nervous system. Resultant plasma levels after subcutaneous (SC), intramuscular (IM), and IV injection are all comparable. After IM or SC injections, morphine plasma levels peak in approximately 20 minutes, and, after oral administration, levels peak in approximately 30 minutes. Morphine is metabolised primarily in the liver and approximately 87% of a dose of morphine is excreted in the urine within 72 hours of administration. Morphine is metabolized primarily into morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) via glucuronidation by phase II metabolism enzyme UDP-glucuronosyl transferase-2B7 (UGT2B7). About 60% of morphine is converted to M3G, and 6–10% is converted to M6G. Not only does the metabolism occur in the liver but it may also take place in the brain and the kidneys. M3G does not undergo opioid receptor binding and has no analgesic effect. M6G binds to μ-receptors and is half as potent an analgesic as morphine in humans. Morphine may also be metabolized into small amounts of normorphine, codeine, and hydromorphone. Metabolism rate is determined by gender, age, diet, genetic makeup, disease state (if any), and use of other medications. The elimination half-life of morphine is approximately 120 minutes, though there may be slight differences between men and women. Morphine can be stored in fat, and, thus, can be detectable even after death. Morphine is able to cross the blood–brain barrier, but, because of poor lipid solubility, protein binding, rapid conjugation with glucuronic acid and ionization, it does not cross easily. Diacetylmorphine, which is derived from morphine, crosses the blood–brain barrier more easily, making it more potent. Morphine and its major metabolites, morphine-3-glucuronide and morphine-6-glucuronide, may be quantitated in blood, plasma, or urine to monitor for abuse, confirm a diagnosis of poisoning or assist in a medicolegal death investigation. Most commercial opiate screening tests based on immunoassays cross-react appreciably with these metabolites. However, chromatographic techniques can easily distinguish and measure each of these substances. When interpreting the results of a test, it is important to consider the morphine usage history of the individual, since a chronic user can develop tolerance to doses that would incapacitate an opiate-naive individual, and the chronic user often has high baseline values of these metabolites in his system. Furthermore, some testing procedures employ a hydrolysis step prior to quantitation that converts the metabolic products to morphine, yielding a result that may be many times larger than with a method that examines each product individually. Interpretation can be confounded by usage of codeine or ingestion of poppy seed foods, either of which leads to the presence of morphine and its conjugated metabolites in a person's biofluids. Most reviews conclude that opioids produce minimal impairment of human performance on tests of sensory, motor, or attentional abilities. However, recent studies have been able to show some impairments caused by morphine, which is not surprising, given that morphine is a central nervous system depressant. Morphine has resulted in impaired functioning on critical flicker frequency (a measure of overall CNS arousal) and impaired performance on the Maddox Wing test (a measure of deviation of the visual axes of the eyes). Few studies have investigated the effects of morphine on motor abilities; a high dose of morphine can impair finger tapping and the ability to maintain a low constant level of isometric force (i.e. fine motor control is impaired), though no studies have shown a correlation between morphine and gross motor abilities. In terms of cognitive abilities, one study has shown that morphine may have a negative impact on anterograde and retrograde memory, but these effects are minimal and are transient. Overall, it seems that acute doses of opioids in non-tolerant subjects produce minor effects in some sensory and motor abilities, and perhaps also in attention and cognition. It is likely that the effects of morphine will be more pronounced in opioid-naive subjects than chronic opioid users. In chronic opioid users, such as those on Chronic Opioid Analgesic Therapy (COAT) for managing severe, chronic pain, behavioural testing has shown normal functioning on perception, cognition, coordination and behaviour in most cases. One recent study analysed COAT patients in order to determine whether they were able to safely operate a motor vehicle. The findings from this study suggest that stable opioid use does not significantly impair abilities inherent in driving (this includes physical, cognitive and perceptual skills). COAT patients showed rapid completion of tasks that require speed of responding for successful performance (e.g., Rey Complex Figure Test) but made more errors than controls. COAT patients showed no deficits in visual-spatial perception and organization (as shown in the WAIS-R Block Design Test) but did show impaired immediate and short-term visual memory (as shown on the Rey Complex Figure Test – Recall). These patients showed no impairments in higher order cognitive abilities (i.e., Planning). COAT patients appeared to have difficulty following instructions and showed a propensity toward impulsive behaviour, yet this did not reach statistical significance. It is important to note that this study reveals that COAT patients have no domain-specific deficits, which supports the notion that chronic opioid use has minor effects on psychomotor, cognitive, or neuropsychological functioning. It is difficult to study the performance effects of morphine without considering why a person is taking morphine. Opioid-naive subjects are volunteers in a pain-free state. However, most chronic-users of morphine use it to manage pain. Pain is a stressor and so it can confound performance results, especially on tests that require a large degree of concentration. Pain is also variable, and will vary over time and from person to person. It is unclear to what extent the stress of pain may cause impairments, and it is also unclear whether morphine is potentiating or attenuating these impairments. Morphine is a benzylisoquinoline alkaloid with two additional ring closures. It has: Most of the licit morphine produced is used to make codeine by methylation. It is also a precursor for many drugs including heroin (3,6-diacetylmorphine), hydromorphone (dihydromorphinone), and oxymorphone (14-hydroxydihydromorphinone); many morphine derivatives are can also be manufactured using thebaine and/or codeine as a starting material. Replacement of the N-methyl group of morphine with an N-phenylethyl group results in a product that is 18 times more powerful than morphine in its opiate agonist potency. Combining this modification with the replacement of the 6-hydroxyl with a 6-methylene group produces a compound some 1,443 times more potent than morphine, stronger than the Bentley compounds such as etorphine (M99, the Immobilon® tranquilliser dart) by some measures. The structure-activity relationship of morphine has been extensively studied. As a result of the extensive study and use of this molecule, more than 250 morphine derivatives (also counting codeine and related drugs) have been developed since the last quarter of the 19th century. These drugs range from 25 percent the analgesic strength of codeine (or slightly more than 2 percent of the strength of morphine) to several thousand times the strength of morphine, to powerful opioid antagonists, including naloxone (Narcan®), naltrexone (Trexan®), diprenorphine (M5050, the reversing agent for the Immobilon® dart) and nalorphine (Nalline®). Some opioid agonist-antagonists, partial agonists, and inverse agonists are also derived from morphine. The receptor-activation profile of the semi-synthetic morphine derivatives varies widely and some, like apomorphine are devoid of narcotic effects. Morphine and most of its derivatives do not exhibit optical isomerism, although some more distant relatives like the morphinan series (levorphanol, dextorphan and the racemic parent chemical dromoran) do, and as noted above stereoselectivity in vivo is an important issue. Morphine-derived agonist–antagonist drugs have also been developed. Elements of the morphine structure have been used to create completely synthetic drugs such as the morphinan family (levorphanol, dextromethorphan and others) and other groups that have many members with morphine-like qualities. The modification of morphine and the aforementioned synthetics has also given rise to non-narcotic drugs with other uses such as emetics, stimulants, antitussives, anticholinergics, muscle relaxants, local anaesthetics, general anaesthetics, and others. Most semi-synthetic opioids, both of the morphine and codeine subgroups, are created by modifying one or more of the following: Both morphine and its hydrated form, CHNOHO, are sparingly soluble in water. In five liters of water, only one gram of the hydrate will dissolve. For this reason, pharmaceutical companies produce sulfate and hydrochloride salts of the drug, both of which are over 300 times more water-soluble than their parent molecule. Whereas the pH of a saturated morphine hydrate solution is 8.5, the salts are acidic. Since they derive from a strong acid but weak base, they are both at about pH = 5; as a consequence, the morphine salts are mixed with small amounts of NaOH to make them suitable for injection. A number of salts of morphine are used, with the most common in current clinical use being the hydrochloride, sulfate, tartrate, and citrate; less commonly methobromide, hydrobromide, hydroiodide, lactate, chloride, and bitartrate and the others listed below. Morphine diacetate, which is another name for heroin, is a Schedule I controlled substance, so it is not used clinically in the United States; it is a sanctioned medication in the United Kingdom and in Canada and some countries in Continental Europe, its use being particularly common (nearly to the degree of the hydrochloride salt) in the United Kingdom. Morphine meconate is a major form of the alkaloid in the poppy, as is morphine pectinate, nitrate, sulphate, and some others. Like codeine, dihydrocodeine and other, especially older, opiates, morphine has been used as the salicylate salt by some suppliers and can be easily compounded, imparting the therapeutic advantage of both the opioid and the NSAID; multiple barbiturate salts of morphine were also used in the past, as was/is morphine valerate, the salt of the acid being the active principle of valerian. Calcium morphenate is the intermediate in various latex and poppy-straw methods of morphine production, more rarely sodium morphenate takes its place. Morphine ascorbate and other salts such as the tannate, citrate, and acetate, phosphate, valerate and others may be present in poppy tea depending on the method of preparation. Morphine valerate produced industrially was one ingredient of a medication available for both oral and parenteral administration popular many years ago in Europe and elsewhere called Trivalin (not to be confused with the current, unrelated herbal preparation of the same name), which also included the valerates of caffeine and cocaine, with a version containing codeine valerate as a fourth ingredient being distributed under the name Tetravalin. Closely related to morphine are the opioids morphine-N-oxide (genomorphine), which is a pharmaceutical that is no longer in common use; and pseudomorphine, an alkaloid that exists in opium, form as degradation products of morphine. The salts listed by the United States Drug Enforcement Administration for reporting purposes, in addition to a few others, are as follows: In the opium poppy the alkaloids are bound to meconic acid. The method is to extract from the crushed plant with diluted sulfuric acid, which is a stronger acid than meconic acid, but not so strong to react with alkaloid molecules. The extraction is performed in many steps (one amount of crushed plant is at least six to ten times extracted, so practically every alkaloid goes into the solution). From the solution obtained at the last extraction step, the alkaloids are precipitated by either ammonium hydroxide or sodium carbonate. The last step is purifying and separating morphine from other opium alkaloids. The somewhat similar Gregory process was developed in the United Kingdom during the Second World War, which begins with stewing the entire plant, in most cases save the roots and leaves, in plain or mildly acidified water, then proceeding through steps of concentration, extraction, and purification of alkaloids. Other methods of processing poppy straw use steam, one or more of several types of alcohol, or other organic solvents. The poppy straw methods predominate in Continental Europe and the British Commonwealth, with the latex method in most common use in India. The latex method can involve either vertical or horizontal slicing of the unripe pods with a two-to five-bladed knife with a guard developed specifically for this purpose to the depth of a fraction of a millimetre and scoring of the pods can be done up to five times. An alternative latex method sometimes used in China in the past is to cut off the poppy heads, run a large needle through them, and collect the dried latex 24 to 48 hours later. Opium poppy contains at least 50 different alkaloids, but most of them are of very low concentration. Morphine is the principal alkaloid in raw opium and constitutes ~8-19% of opium by dry weight (depending on growing conditions). Some purpose-developed strains of poppy now produce opium that is up to 26 percent morphine by weight. A rough rule of thumb to determine the morphine content of pulverised dried poppy straw is to divide the percentage expected for the strain or crop via the latex method by eight or an empirically determined factor, which is often in the range of 5 to 15. The Norman strain of P. Somniferum, also developed in Tasmania, produces down to 0.04 percent morphine but with much higher amounts of thebaine and oripavine, which can be used to synthesise semi-synthetic opioids as well as other drugs like stimulants, emetics, opioid antagonists, anticholinergics, and smooth-muscle agents. In the 1950s and 1960s, Hungary supplied nearly 60% of Europe's total medication-purpose morphine production. To this day, poppy farming is legal in Hungary, but poppy farms are limited by law to 2 acres (8,100 m2). It is also legal to sell dried poppy in flower shops for use in floral arrangements. It was announced in 1973 that a team at the National Institutes of Health in the United States had developed a method for total synthesis of morphine, codeine, and thebaine using coal tar as a starting material. A shortage in codeine-hydrocodone class cough suppressants (all of which can be made from morphine in one or more steps, as well as from codeine or thebaine) was the initial reason for the research. Most morphine produced for pharmaceutical use around the world is actually converted into codeine as the concentration of the latter in both raw opium and poppy straw is much lower than that of morphine; in most countries, the usage of codeine (both as end-product and precursor) is at least equal or greater than that of morphine on a weight basis. Morphine can be isolated from whole blood samples by solid phase extraction (SPE) and detected using liquid chromatography-mass spectrometry (LC-MS). The morphine is biosynthesized from the tetrahydroisoquinoline reticuline. It is converted into salutaridine, thebaine, and oripavine. The involucrated enzymes in this process are the salutaridine synthase, salutaridine:NADPH 7-oxidoreductase and the codeinone reductase An opium-based elixir has been ascribed to alchemists of Byzantine times, but the specific formula was lost during the Ottoman conquest of Constantinople (Istanbul). Around 1522, Paracelsus made reference to an opium-based elixir that he called laudanum from the Latin word laudare, meaning "to praise" He described it as a potent painkiller, but recommended that it be used sparingly. In the late eighteenth century, when the East India Company gained a direct interest in the opium trade through India, another opiate recipe called laudanum became very popular among physicians and their patients. Morphine was discovered as the first active alkaloid extracted from the opium poppy plant in December 1804 in Paderborn, Germany, by Friedrich Sertürner. The drug was first marketed to the general public by Sertürner and Company in 1817 as an analgesic, and also as a treatment for opium and alcohol addiction. Commercial production began in Darmstadt, Germany in 1827 by the pharmacy that became the pharmaceutical company Merck, with morphine sales being a large part of their early growth. Later it was found that morphine was more addictive than either alcohol or opium, and its extensive use during the American Civil War allegedly resulted in over 400,000 sufferers from the "soldier's disease" of morphine addiction. This idea has been a subject of controversy, as there have been suggestions that such a disease was in fact a fabrication; the first documented use of the phrase "soldier's disease" was in 1915. Diacetylmorphine (better known as heroin) was synthesized from morphine in 1874 and brought to market by Bayer in 1898. Heroin is approximately 1.5 to 2 times more potent than morphine weight for weight. Due to the lipid solubility of diacetylmorphine, it is able to cross the blood–brain barrier faster than morphine, subsequently increasing the reinforcing component of addiction. Using a variety of subjective and objective measures, one study estimated the relative potency of heroin to morphine administered intravenously to post-addicts to be 1.80–2.66 mg of morphine sulfate to 1 mg of diamorphine hydrochloride (heroin). Morphine became a controlled substance in the US under the Harrison Narcotics Tax Act of 1914, and possession without a prescription in the US is a criminal offense. Morphine was the most commonly abused narcotic analgesic in the world until heroin was synthesized and came into use. In general, until the synthesis of dihydromorphine (ca. 1900), the dihydromorphinone class of opioids (1920s), and oxycodone (1916) and similar drugs, there were no other drugs in the same efficacy range as opium, morphine, and heroin, with synthetics still several years away (pethidine was invented in Germany in 1937) and opioid agonists among the semi-synthetics were analogues and derivatives of codeine such as dihydrocodeine (Paracodin), ethylmorphine (Dionine), and benzylmorphine (Peronine). Even today, morphine is the most sought after prescription narcotic by heroin addicts when heroin is scarce, all other things being equal; local conditions and user preference may cause hydromorphone, oxymorphone, high-dose oxycodone, or methadone as well as dextromoramide in specific instances such as 1970s Australia, to top that particular list. The stop-gap drugs used by the largest absolute number of heroin addicts is probably codeine, with significant use also of dihydrocodeine, poppy straw derivatives like poppy pod and poppy seed tea, propoxyphene, and tramadol. The structural formula of morphine was determined by 1925 by Robert Robinson. At least three methods of total synthesis of morphine from starting materials such as coal tar and petroleum distillates have been patented, the first of which was announced in 1952, by Dr. Marshall D. Gates, Jr. at the University of Rochester. Still, the vast majority of morphine is derived from the opium poppy by either the traditional method of gathering latex from the scored, unripe pods of the poppy, or processes using poppy straw, the dried pods and stems of the plant, the most widespread of which was invented in Hungary in 1925 and announced in 1930 by the chemist János Kábay. In 2003, there was discovery of endogenous morphine occurring naturally in the human body. Thirty years of speculation were made on this subject because there was a receptor that, it appeared, reacted only to morphine: the mu3 opiate receptor in human tissue. Human cells that form in reaction to cancerous neuroblastoma cells have been found to contain trace amounts of endogenous morphine. The euphoria, comprehensive alleviation of distress and therefore all aspects of suffering, promotion of sociability and empathy, "body high", and anxiolysis provided by narcotic drugs including the opioids can cause the use of high doses in the absence of pain for a protracted period, which can impart a morbid craving for the drug in the user. Being the prototype of the entire opioid class of drugs means that morphine has properties that may lend it to misuse. Morphine addiction is the model upon which the current perception of addiction is based. Animal and human studies and clinical experience back up the contention that morphine is one of the most euphoric of drugs on earth, and via all but the IV route heroin and morphine cannot be distinguished according to studies because heroin is a prodrug for the delivery of systemic morphine. Chemical changes to the morphine molecule yield other euphorigenics such as dihydromorphine, hydromorphone (Dilaudid, Hydal), and oxymorphone (Numorphan, Opana), as well as the latter three's methylated equivalents dihydrocodeine, hydrocodone, and oxycodone, respectively; in addition to heroin, there are dipropanoylmorphine, diacetyldihydromorphine, and other members of the 3,6 morphine diester category like nicomorphine and other similar semi-synthetic opiates like desomorphine, hydromorphinol, etc. used clinically in many countries of the world but in many cases also produced illicitly in rare instances. In general, misuse of morphine entails taking more than prescribed or outside of medical supervision, injecting oral formulations, mixing it with unapproved potentiators such as alcohol, cocaine, and the like, and/or defeating the extended-release mechanism by chewing the tablets or turning into a powder for snorting or preparing injectables. The latter method can be every bit as time-consuming and involved as traditional methods of smoking opium. This and the fact that the liver destroys a large percentage of the drug on the first pass impacts the demand side of the equation for clandestine re-sellers, as many customers are not needle users and may have been disappointed with ingesting the drug orally. As morphine is generally as hard or harder to divert than oxycodone in a lot of cases, morphine in any form is uncommon on the street, although ampoules and phials of morphine injection, pure pharmaceutical morphine powder, and soluble multi-purpose tablets are very popular where available. Morphine is also available in a paste that is used in the production of heroin, which can be smoked by itself or turned to a soluble salt and injected; the same goes for the penultimate products of the Kompot (Polish Heroin) and black tar processes. Poppy straw as well as opium can yield morphine of purity levels ranging from poppy tea to near-pharmaceutical-grade morphine by itself or with all of the more than 50 other alkaloids. It also is the active narcotic ingredient in opium and all of its forms, derivatives, and analogues as well as forming from breakdown of heroin and otherwise present in many batches of illicit heroin as the result of incomplete acetylation. Morphine is known on the street and elsewhere as M, sister morphine, Vitamin M, morpho, etc. MS Contin tablets are known as misties, and the 100 mg extended-release tablets as greys and blockbusters. The "speedball" can use morphine as the narcotic component, which is combined with cocaine, amphetamines, methylphenidate, or similar drugs. "Blue Velvet" is a combination of morphine with the antihistamine tripelennamine (Pyrabenzamine, PBZ, Pelamine) taken by injection, or less commonly the mixture when swallowed or used as a retention enema; the name is also known to refer to a combination of tripelennamine and dihydrocodeine or codeine tablets or syrups taken by mouth. "Morphia" is an older official term for morphine also used as a slang term. "Driving Miss Emma" is intravenous administration of morphine. Multi-purpose tablets (readily soluble hypodermic tablets that can also be swallowed or dissolved under the tongue or betwixt the cheek and jaw) are known, as are some brands of hydromorphone, as Shake & Bake or Shake & Shoot. Morphine can be smoked, especially diacetylmorphine (heroin), the most common method being the "Chasing The Dragon" method. To perform a relatively crude acetylation to turn the morphine into heroin and related drugs immediately prior to use is known as AAing (for Acetic Anhydride) or home-bake, and the output of the procedure also known as home-bake or, Blue Heroin (not to be confused with Blue Magic heroin, or the linctus known as Blue Morphine or Blue Morphone, or the Blue Velvet mixture described above). Morphine is marketed under many different brand names in various parts of the world: Morphine is a precursor in the manufacture in a large number of opioids such as dihydromorphine, hydromorphone, nicomorphine, and heroin as well as codeine, which itself has a large family of semi-synthetic derivatives. Morphine is commonly treated with acetic anhydride and ignited to yield heroin. Throughout Europe there is growing acceptance within the medical community of the use of slow release oral morphine as a substitution treatment alternative to methadone and buprenorphine for patients not able to tolerate the side-effects of buprenorphine and methadone. Slow-release oral morphine has been in widespread use for opiate maintenance therapy in Austria, Bulgaria, and Slovakia for many years and it is available on a small scale in many other countries including the UK. The long-acting nature of slow-release morphine mimics that of buprenorphine because the sustained blood levels are relatively flat so there is no "high" per se that a patient would feel but rather a sustained feeling of wellness and avoidance of withdrawal symptoms. For patients sensitive to the side-effects that in part may be a result of the unnatural pharmacological actions of buprenorphine and methadone, slow-release oral morphine formulations offer a promising future for use managing opiate addiction. The pharmacology of heroin and morphine is identical except the two acetyl groups increase the lipid solubility of the heroin molecule, causing heroin to cross the blood–brain barrier and enter the brain more rapidly in injection. Once in the brain, these acetyl groups are removed to yield morphine, which causes the subjective effects of heroin. Thus, heroin may be thought of as a more rapidly acting form of morphine. Illicit morphine is rarely produced from codeine found in over-the-counter cough and pain medicines. This demethylation reaction is often performed using pyridine and hydrochloric acid. Another source of illicit morphine comes from the extraction of morphine from extended-release morphine products, such as MS-Contin. Morphine can be extracted from these products with simple extraction techniques to yield a morphine solution that can be injected. As an alternative, the tablets can be crushed and snorted, injected or swallowed, although this provides much less euphoria but retains some of the extended-release effect, and the extended-release property is why MS-Contin is used in some countries alongside methadone, dihydrocodeine, buprenorphine, dihydroetorphine, piritramide, levo-alpha-acetylmethadol (LAAM), and special 24-hour formulations of hydromorphone for maintenance and detoxification of those physically dependent on opioids. Another means of using or misusing morphine is to use chemical reactions to turn it into heroin or another stronger opioid. Morphine can, using a technique reported in New Zealand (where the initial precursor is codeine) and elsewhere known as home-bake, be turned into what is usually a mixture of morphine, heroin, 3-monoacetylmorphine, 6-monoacetylmorphine, and codeine derivatives like acetylcodeine if the process is using morphine made from demethylating codeine. Since heroin is one of a series of 3,6 diesters of morphine, it is possible to convert morphine to nicomorphine (Vilan) using nicotinic anhydride, dipropanoylmorphine with propionic anhydride, dibutanoylmorphine and disalicyloylmorphine with the respective acid anhydrides. Glacial acetic acid can be used to obtain a mixture high in 6-monoacetylmorphine, niacin (vitamin B3) in some form would be precursor to 6-nicotinylmorphine, salicylic acid may yield the salicyoyl analogue of 6-MAM, and so on. The clandestine conversion of morphine to ketones of the hydromorphone class or other derivatives like dihydromorphine (Paramorfan), desomorphine (Permonid), metopon, etc. and codeine to hydrocodone (Dicodid), dihydrocodeine (Paracodin), etc. is more involved, time-consuming, requires lab equipment of various types, and usually requires expensive catalysts and large amounts of morphine at the outset and is less common but still has been discovered by authorities in various ways during the last 20 years or so. Dihydromorphine can be acetylated into another 3,6 morphine diester, namely diacetyldihydromorphine (Paralaudin), and hydrocodone into thebacon. Although morphine is cheap, people in poorer countries often do not have access to it. According to a 2005 estimate by the International Narcotics Control Board, six countries (Australia, Canada, France, Germany, the United Kingdom, and the United States) consume 79 percent of the world’s morphine. The less affluent countries, accounting for 80 percent of the world's population, consumed only about 6 percent of the global morphine supply. Some countries import virtually no morphine, and in others the drug is rarely available even for relieving severe pain while dying. Experts in pain management attribute the under-distribution of morphine to an unwarranted fear of the drug's potential for addiction and abuse. While morphine is clearly addictive, Western doctors believe it is worthwhile to use the drug and then wean the patient off when the treatment is over. M: CNS anat (n/s/m/p/4/e/b/d/c/a/f/l/g)/phys/devp noco (m/d/e/h/v/s)/cong/tumr, sysi/epon, injr proc, drug (N1A/2AB/C/3/4/7A/B/C/D)

Endo Pharmaceuticals
Endo Health Solutions Inc. is an American pharmaceutical company. It was created as a result of a management buyout from DuPont Merck in 1997. Three DuPont Merck executives (Carol A. Ammon, Chairman, President & CEO, and Mariann T. MacDonald, Executive Vice President, Operations, along with another colleague) purchased all of Endo Laboratories L.L.C.'s generic products along with 12 important brand products, including Percocet, Percodan, and Opana. The new company was called Endo Pharmaceuticals Inc. On 23rd May 2012, Endo's shareholders approved a resolution to change the company's name to Endo Health Solutions Inc.. Endo acquired Algos Pharmaceutical Corporation through a merger in July 2000 and began to trade publicly (NASDAQ: ENDP). Endo successfully completed a secondary offering for a total of 12,925,000 shares of its common stock in Oct 2001. The net proceeds were used to pay existing bank debt. Endo is a specialty pharmaceutical company engaged in the research, development, sale and marketing of prescription pharmaceuticals used primarily to treat and manage pain. Endo contracts some production and quality control testing from Novartis, at the Novartis manufacturing facility in Lincoln, Nebraska. Prior to its December 2011 shutdown, this particular Novartis manufacturing facility made all Excedrin distributed in the United States. In 2009, Endo bought Indevus Pharmaceuticals to diversify into endocrinology and oncology. The company entered the male hypogonadism market later in 2010 with FORTESTA 2% gel. Source: The agreement of 6 January 2006 for Endo Pharmaceuticals to market Synera (lidocaine plus tetracaine patch) was terminated on 31 July 2008.  Endo is no longer involved with the Synera patch.  Zars Pharmaceuticals is the patent holder for Synera. The rights to Synera passed to Nuvo Research of Canada in May, 2011 upon the acquisition of ZARS Pharmaceuticals by Nuvo Research.

Chronic pain
Chronic pain is pain that has lasted for a long time. In medicine, the distinction between acute and chronic pain has traditionally been determined by an arbitrary interval of time since onset; the two most commonly used markers being 3 months and 6 months since onset, though some theorists and researchers have placed the transition from acute to chronic pain at 12 months. Others apply acute to pain that lasts less than 30 days, chronic to pain of more than six months duration, and subacute to pain that lasts from one to six months. A popular alternative definition of chronic pain, involving no arbitrarily fixed durations is "pain that extends beyond the expected period of healing". Chronic pain may be divided into "nociceptive" (caused by activation of nociceptors), and "neuropathic" (caused by damage to or malfunction of the nervous system). Nociceptive pain may be divided into "superficial" and "deep", and deep pain into "deep somatic" and "visceral". Superficial pain is initiated by activation of nociceptors in the skin or superficial tissues. Deep somatic pain is initiated by stimulation of nociceptors in ligaments, tendons, bones, blood vessels, fasciae and muscles, and is dull, aching, poorly-localized pain. Visceral pain originates in the viscera (organs). Visceral pain may be well-localized, but often it is extremely difficult to locate, and several visceral regions produce "referred" pain when damaged or inflamed, where the sensation is located in an area distant from the site of pathology or injury. Neuropathic pain is divided into "peripheral" (originating in the peripheral nervous system) and "central" (originating in the brain or spinal cord). Peripheral neuropathic pain is often described as "burning", "tingling", "electrical", "stabbing", or "pins and needles". Under persistent activation nociceptive transmission to the dorsal horn may induce a wind up phenomenon. This induces pathological changes that lower the threshold for pain signals to be transmitted. In addition it may generate nonnociceptive nerve fibers to respond to pain signals. Nonnociceptive nerve fibers may also be able to generate and transmit pain signals. In chronic pain this process is difficult to reverse or eradicate once established. Chronic pain of different etiologies has been characterized as a disease affecting brain structure and function. Magnetic resonance imaging studies have shown abnormal anatomical and functional connectivity, even during rest involving areas related to the processing of pain. Also, persistent pain has been shown to cause grey matter loss, reversible once the pain has resolved. These structural changes can be explained by the phenomenon known as neuroplasticity. In the case of chronic pain, the somatototic representation of the body is inappropriately reorganized following peripheral and central sensitization. This maladaptative change results in the experience of allodynia and/or hyperalgesia. Brain activity in individuals suffering from chronic pain, measured via electroencephalogram (EEG), has been demonstrated to be altered, suggesting pain-induced neuroplastic changes. More specifically, the relative beta activity (compared to the rest of the brain) is increased, the relative alpha activity is decreased, and the theta activity both absolutely and relatively is diminished. Complete and sustained remission of many neuropathies and most idiopathic chronic pain (pain that extends beyond the expected period of healing, or chronic pain that has no known underlying pathology) is rarely achieved, but much can be done to reduce suffering and improve quality of life. Pain management is the branch of medicine employing an interdisciplinary approach to the relief of pain and improvement in the quality of life of those living with pain. The typical pain management team includes medical practitioners, clinical psychologists, physiotherapists, occupational therapists, and nurse practitioners. Acute pain usually resolves with the efforts of one practitioner; however, the management of chronic pain frequently requires the coordinated efforts of the treatment team. Psychological treatments including cognitive behavioral therapy and acceptance and commitment therapy have been shown effective for improving quality of life in those suffering from chronic pain. Clinical hypnosis, including self-hypnosis, has been shown effective not only for improving quality of life, but for direct improvement of chronic pain symptoms. The emergence of studies relating chronic pain to neuroplasticity also suggest the utilization of neurofeedback rehabilitation techniques to resolve maladaptive cortical changes and patterns. The proposed goal of neurofeedback intervention is to abolish maladaptive neuroplastic changes made as a result of chronic nociception, as measured by abnormal EEG, and thereby relieve the individual's pain. However, this field of research lacks randomized control trials, and therefore requires further investigation. In a recent large-scale telephone survey of 15 European countries and Israel, 19% of respondents over 18 years of age had suffered pain for more than 6 months, including the last month, and more than twice in the last week, with pain intensity of 5 or more for the last episode, on a scale of 1(no pain) to 10 (worst imaginable). 4839 of these respondents with chronic pain were interviewed in depth. Sixty six percent scored their pain intensity at moderate (5–7), and 34% at severe (8–10); 46% had constant pain, 56% intermittent; 49% had suffered pain for 2–15 years; and 21% had been diagnosed with depression due to the pain. Sixty one percent were unable or less able to work outside the home, 19% had lost a job, and 13% had changed jobs due to their pain. Forty percent had inadequate pain management and less than 2% were seeing a pain management specialist. In a systematic literature review published by the International Association for the Study of Pain (IASP), 13 chronic pain studies from various countries around the world were analyzed.  (Of the 13 studies, there were three in the United Kingdom, two in Australia, one each in France, the Netherlands, Israel, Canada, Scotland, Spain, and Sweden, and a multinational.) The authors found that the prevalence of chronic pain was very high and that chronic pain consumes a large amount of healthcare resources around the globe. Chronic pain afflicted women at a higher rate than men. They determined that the prevalence of chronic pain varied from 10.1% to 55.2% of the population. In the United States, the prevalence of chronic pain has been estimated to be approximately 30%. According to the Institute of Medicine, there are about 116 million Americans living with chronic pain. The Mayday Fund estimate of 70 million Americans with chronic pain is slightly more conservative. In an internet study, the prevalence of chronic pain in the United States was calculated to be 30.7% of the population: 34.3% for women and 26.7% for men. These estimates are in reasonable agreement and indicate a prevalence of chronic pain in the US that is relatively comparable to that of other countries.][ Chronic pain is associated with higher rates of depression and anxiety. Sleep disturbance, and insomnia due to medication and illness symptoms are often experienced by those with chronic pain. Chronic pain may contribute to decreased physical activity due to fear of exacerbating pain. Two of the most frequent personality profiles found in chronic pain patients by the Minnesota Multiphasic Personality Inventory (MMPI) are the conversion V and the neurotic triad. The conversion V personality, so called because the higher scores on MMPI scales 1 and 3, relative to scale 2, form a "V" shape on the graph, expresses exaggerated concern over body feelings, develops bodily symptoms in response to stress, and often fails to recognize their own emotional state, including depression. The neurotic triad personality, scoring high on scales 1, 2 and 3, also expresses exaggerated concern over body feelings and develops bodily symptoms in response to stress, but is demanding and complaining. Some investigators have argued that it is this neuroticism that causes acute pain to turn chronic, but clinical evidence points the other way, to chronic pain causing neuroticism. When long term pain is relieved by therapeutic intervention, scores on the neurotic triad and anxiety fall, often to normal levels. Self-esteem, often low in chronic pain patients, also shows striking improvement once pain has resolved. Chronic pain's impact on cognition is an under-researched area, but several tentative conclusions have been published. Most chronic pain patients complain of cognitive impairment, such as forgetfulness, difficulty with attention, and difficulty completing tasks. Objective testing has found that people in chronic pain tend to experience impairment in attention, memory, mental flexibility, verbal ability, speed of response in a cognitive task, and speed in executing structured tasks. In 2007, Shulamith Kreitler and David Niv advised clinicians to assess cognitive function in chronic pain patients in order to more precisely monitor therapeutic outcomes, and tailor treatment to address this aspect of the pain experience. M: CNS anat (n/s/m/p/4/e/b/d/c/a/f/l/g)/phys/devp noco (m/d/e/h/v/s)/cong/tumr, sysi/epon, injr proc, drug (N1A/2AB/C/3/4/7A/B/C/D) M: PNS anat (h/r/t/c/b/l/s/a)/phys (r)/devp/prot/nttr/nttm/ntrp noco/auto/cong/tumr, sysi/epon, injr proc, drug (N1B)

Pandiagonal magic square
A pandiagonal magic square or panmagic square (also diabolic square, diabolical square or diabolical magic square) is a magic square with the additional property that the broken diagonals, i.e. the diagonals that wrap round at the edges of the square, also add up to the magic constant. A pandiagonal magic square remains pandiagonally magic not only under rotation or reflection, but also if a row or column is moved from one side of the square to the opposite side. As such, an n×n pandiagonal magic square can be regarded as having 8n2 orientations. The smallest non-trivial pandiagonal magic squares are 4×4 squares. In 4×4 panmagic squares, the magic constant of 34 can be seen in a number of patterns in addition to the rows, columns and diagonals: Thus of the 86 possible sums adding to 34, 52 of them form regular patterns, compared with 10 for an ordinary 4×4 magic square. There are only three distinct 4×4 pandiagonal magic squares, namely the one above and the following: In any 4×4 pandiagonal magic square, any two numbers at the opposite corners of a 3×3 square add up to 17. Consequently, no 4×4 panmagic squares are associative. There are many 5×5 pandiagonal magic squares. Unlike 4×4 panmagic squares, these can be associative. The following is a 5×5 associative panmagic square: In addition to the rows, columns, and diagonals, a 5×5 pandiagonal magic square also shows its magic sum in four "quincunx" patterns, which in the above example are: Each of these quincunxes can be translated to other positions in the square by cyclic permutation of the rows and columns (wrapping around), which in a pandiagonal magic square does not affect the equality of the magic sums. This leads to 100 quincunx sums, including broken quincunxes analogous to broken diagonals. The quincunx sums can be proved by taking linear combinations of the row, column, and diagonal sums. Consider the panmagic square with magic sum Z. To prove the quincunx sum A+E+M+U+Y = Z (corresponding to the 20+2+13+24+6 = 65 example given above), one adds together the following: From this sum the following are subtracted: The net result is 5A+5E+5M+5U+5Y = 5Z, which divided by 5 gives the quincunx sum. Similar linear combinations can be constructed for the other quincunx patterns H+L+M+N+R, C+K+M+O+W, and G+I+M+Q+S. No panmagic square exists of order 3 or 4n+2. So no 6×6 panmagic square exists. A (6n±1)×(6n±1) panmagic square can be built by the following algorithm. Example: Example: Example: Example: A + (6n±1)×AT - (6n±1) A 4n×4n panmagic square can be built by the following algorithm. Example: Example: Example: Example: Example: A + 4n×B - 4n If you build a 4n×4n pandiagonal magic square with this algorithm then every 2×2 square in the 4n×4n square will have the same sum. Therefore many symmetric patterns of 4n cells have the same sum as any row and any column of the 4n×4n square. Especially each 2n×2 and each 2×2n rectangle will have the same sum as any row and any column of the 4n×4n square. The 4n×4n square is also a Most-perfect magic square. A (6n+3)×(6n+3) panmagic square with n>0 can be built by the following algorithm. Examples: Example: Example: Example: Example: Example: A + (6n+3)×AT – (6n+3)

Time release technology
Time release technology (also known as sustained-release (SR), sustained-action (SA), extended-release (ER, XR, XL), timed-release (TR), controlled-release (CR), modified release (MR), or continuous-release (Contin)) is a mechanism used in pill tablets or capsules to dissolve a drug over time in order to be released slower and steadier into the bloodstream while having the advantage of being taken at less frequent intervals than immediate-release (IR) formulations of the same drug. Today, most time-release drugs are formulated so that 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 the matrix. Some drugs are enclosed in polymer-based tablets with a laser-drilled hole on one side and a porous membrane on the other side. Stomach acids push through the porous membrane, thereby pushing the drug out through the laser-drilled hole. In time, the entire drug dose releases into the system while the polymer container remains intact, to be excreted later through normal digestion. 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 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 you are able to obtain more consistent and replicable dissolution rates in a convenient format you can mix and match with other instant release pharmaceutical ingredients in to any two piece gelatin capsule. There are certain considerations for the formation of sustained-release formulation: 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 the microcapsules inside are swallowed whole.
Alcohols Ketones Euphoriants Phenols Oxycodone Hydrogen chloride Tapentadol Percodan Disaster Accident Chemistry Organic chemistry Morphinans Health Medical Pharma Hospitality Recreation Politics

Related Websites:

Terms of service | About