An analgesic drug , also called simply an analgesic , antalgic , pain reliever , or painkiller , is any member of the group of drugs used for pain management . Analgesics are conceptually distinct from anesthetics , which temporarily reduce, and in some instances eliminate, sensation , although analgesia and anesthesia are neurophysiologically overlapping and thus various drugs have both analgesic and anesthetic effects.
120-439: Paracetamol , or acetaminophen , is a non-opioid analgesic and antipyretic agent used to treat fever and mild to moderate pain . It is a widely used over-the-counter medication . Common brand names include Tylenol and Panadol . Paracetamol relieves pain in both acute mild migraine and episodic tension headache . At a standard dose, paracetamol slightly reduces fever; it is inferior to ibuprofen in that respect, and
240-503: A "highlighted" one for self-medication of tension headache, with paracetamol/caffeine combination being a "remedy of first choice", and paracetamol a "remedy of second choice". Pain after a dental surgery provides a reliable model for the action of analgesics on other kinds of acute pain. For the relief of such pain, paracetamol is inferior to ibuprofen. Full therapeutic doses of nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen, naproxen or diclofenac are clearly more efficacious than
360-409: A blood meal from the infected host then propagates the virus in the cells lining its gut. Over the next few days, the virus spreads to other tissues including the mosquito's salivary glands and is released into its saliva. Next time the mosquito feeds, the infectious saliva will be injected into the bloodstream of its victim, thus spreading the disease. The virus seems to have no detrimental effect on
480-530: A cream, ointment, or gel. Topical nonsteroidal anti-inflammatory drugs provide pain relief in common conditions such as muscle sprains and overuse injuries. Since the side effects are also lesser, topical preparations could be preferred over oral medications in these conditions. Some novel and investigational analgesics include subtype-selective voltage-gated sodium channel blockers such as funapide and raxatrigine , as well as multimodal agents such as ralfinamide . Dengue fever Dengue fever
600-459: A degree of dose dependence. The association between paracetamol use and asthma in children has been a matter of controversy. However, the most recent research suggests that there is no association, and that the frequency of asthma exacerbations in children after paracetamol is the same as after another frequently used pain killer, ibuprofen. In recommended doses, the side effects of paracetamol are mild to non-existent. In contrast to aspirin, it
720-504: A diagnosis of dengue. During the first few days of infection, enzyme-linked immunosorbent assay ( ELISA ) can be used to detect the NS1 antigen ; however this antigen is produced by all flaviviruses. Four or five days into the infection, it is possible to reliably detect anti-dengue IgM antibodies, but this does not determine the serotype. Nucleic acid amplification tests provide the most reliable method of diagnosis. As of July 2024, there
840-463: A different type increases the risk of severe complications. The symptoms of dengue resemble many other diseases including malaria , influenza , and Zika . Blood tests are available to confirm the diagnosis including detecting viral RNA , or antibodies to the virus. There is no specific treatment for dengue fever. In mild cases, treatment is focused on treating pain symptoms. Severe cases of dengue require hospitalisation; treatment of acute dengue
960-405: A dose-dependent anticonvulsant activity against pentylenetetrazol-induced seizures in mice. After being taken by mouth, paracetamol is rapidly absorbed from the small intestine , while absorption from the stomach is negligible. Thus, the rate of absorption depends on stomach emptying. Food slows the stomach emptying and absorption, but the total amount absorbed stays the same. In the same subjects,
1080-595: A few days as the fever subsides. Leakage of plasma from the capillaries results in extreme low blood pressure and hypovolemic shock ; Patients with severe plasma leakage may have fluid accumulation in the lungs or abdomen , insufficient protein in the blood , or thickening of the blood . Severe dengue is a medical emergency which can cause damage to organs, leading to multiple organ failure and death. Mild cases of dengue fever can easily be confused with several common diseases including Influenza , measles , chikungunya , and zika . Dengue, chikungunya and zika share
1200-636: A majority of adult overdoses are linked to suicide attempts, many cases are accidental, often due to the use of more than one paracetamol-containing product over an extended period. Paracetamol toxicity has become the foremost cause of acute liver failure in the United States by 2003, and as of 2005, paracetamol accounted for most drug overdoses in the United States, the United Kingdom, Australia, and New Zealand. As of 2004, paracetamol overdose resulted in more calls to poison control centers in
1320-435: A patient is routinely switched between two or more non-cross-tolerant opioid medications in order to prevent exceeding safe dosages in the attempt to achieve an adequate analgesic effect. Opioid tolerance should not be confused with opioid-induced hyperalgesia . The symptoms of these two conditions can appear very similar but the mechanism of action is different. Opioid-induced hyperalgesia is when exposure to opioids increases
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#17327979695821440-537: A person, the virus enters the skin together with the mosquito's saliva. The virus infects nearby skin cells called keratinocytes , as well as specialized immune cell located in the skin, called a Langerhans cells . The Langerhans cells migrate to the lymph nodes , where the infection spreads to white blood cells , and reproduces inside the cells while they move throughout the body. The white blood cells respond by producing several signaling proteins, such as cytokines and interferons , which are responsible for many of
1560-454: A phenol derivate, e.g. salicylic acid, to form an indophenol dye under oxidization by air. Analgesic Analgesic choice is also determined by the type of pain: For neuropathic pain , recent research has suggested that classes of drugs that are not normally considered analgesics, such as tricyclic antidepressants and anticonvulsants may be considered as an alternative. Various analgesics, such as many NSAIDs , are available over
1680-421: A possible increase of asthma and developmental and reproductive disorders in the offspring of women with prolonged use of paracetamol during pregnancy. Paracetamol use by the mother during pregnancy is associated with an increased risk of childhood asthma , but so are the maternal infections for which paracetamol may be used, and separating these influences is difficult. Paracetamol, in a small scale meta-analysis
1800-490: A result, it has been described as over-prescribed for this application. In addition, low-quality clinical data indicates that when used for the common cold , paracetamol may relieve a stuffed or runny nose, but not other cold symptoms such as sore throat , malaise , sneezing , or cough . For people in critical care , paracetamol decreases body temperature by only 0.2–0.3 °C more than control interventions and has no effect on their mortality . It did not change
1920-401: A short course of antiemetics such as phenergan ). Pruritus (itching) may require switching to a different opioid. Constipation occurs in almost all patients on opioids, and laxatives ( lactulose , macrogol -containing or co-danthramer) are typically co-prescribed. When used appropriately, opioids and other central analgesics are safe and effective; however, risks such as addiction and
2040-636: A small proportion it is life-threatening. The incubation period (time between exposure and onset of symptoms) ranges from 3 to 14 days, but most often it is 4 to 7 days. The characteristic symptoms of mild dengue are sudden-onset fever, headache (typically located behind the eyes), muscle and joint pains, nausea, vomiting, swollen glands and a rash. If this progresses to severe dengue the symptoms are severe abdominal pain, persistent vomiting, rapid breathing, bleeding gums or nose, fatigue, restlessness, blood in vomit or stool, extreme thirst, pale and cold skin, and feelings of weakness. The course of infection
2160-477: A ten fold increase between 2010 and 2019 (from 500,000 to 5 million recorded cases). This increase is tied closely to the increasing range of Aedes mosquitoes, which is attributed to a combination of urbanization , population growth, and an increasingly warm climate . In endemic areas, dengue infections peak when rainfall is optimal for mosquito breeding. In October 2023, the first confirmed symptomatic case of locally acquired dengue (i.e. not while travelling) in
2280-451: Is 0.8–2.5%, and with adequate treatment this is less than 1%. However, those who develop significantly low blood pressure may have a fatality rate of up to 26%. The risk of death among children less than five years old is four times greater than among those over the age of 10. Elderly people are also at higher risk of a poor outcome. As of March 2023, dengue is endemic in more than 100 countries with cases reported in every continent with
2400-422: Is a mosquito-borne disease caused by dengue virus , prevalent in tropical and subtropical areas. It is frequently asymptomatic ; if symptoms appear they typically begin 3 to 14 days after infection. These may include a high fever , headache , vomiting , muscle and joint pains , and a characteristic skin itching and skin rash . Recovery generally takes two to seven days. In a small proportion of cases,
2520-542: Is a partial agonist of the μ-opioid receptor, and tramadol is a serotonin norepinephrine reuptake inhibitor (SNRI) with weak μ-opioid receptor agonist properties. Tramadol is structurally closer to venlafaxine than to codeine and delivers analgesia by not only delivering "opioid-like" effects (through mild agonism of the mu receptor ) but also by acting as a weak but fast-acting serotonin releasing agent and norepinephrine reuptake inhibitor . Tapentadol , with some structural similarities to tramadol, presents what
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#17327979695822640-459: Is a live attenuated vaccine containing the four serotypes of dengue virus, administered subcutaneously as two doses three months apart. The World Health Organization 's International Classification of Diseases divides dengue fever into two classes: uncomplicated and severe. Severe dengue is defined as that associated with severe bleeding, severe organ dysfunction, or severe plasma leakage. Severe dengue can develop suddenly, sometimes after
2760-511: Is also available intravenously . Effects last between two and four hours. Paracetamol is classified as a mild analgesic. Paracetamol is generally safe at recommended doses. Nonsteroidal anti-inflammatory drugs (usually abbreviated to NSAIDs), are a drug class that groups together drugs that decrease pain and lower fever , and, in higher doses, decrease inflammation . The most prominent members of this group of drugs, aspirin , ibuprofen and naproxen , Diclofenac are all available over
2880-480: Is also used for painful mouth sores and to numb areas for dental work and minor medical procedures. In February 2007 the FDA notified consumers and healthcare professionals of the potential hazards of topical anesthetics entering the bloodstream when applied in large doses to the skin without medical supervision. These topical anesthetics contain anesthetic drugs such as lidocaine, tetracaine, benzocaine, and prilocaine in
3000-428: Is an RNA virus of the family Flaviviridae ; genus Flavivirus . Other members of the same genus include yellow fever virus , West Nile virus , and Zika virus . Dengue virus genome (genetic material) contains about 11,000 nucleotide bases , which code for the three structural protein molecules (C, prM and E) that form the virus particle and seven other protein molecules that are required for replication of
3120-778: Is associated with 1.9 times higher risk of peptic ulcer. Those who take it regularly at a higher dose (more than 2–3 g daily) are at much higher risk (3.6–3.7 times) of gastrointestinal bleeding and other bleeding events. Meta-analyses suggest that paracetamol may increase the risk of kidney impairment by 23 % and kidney cancer by 28 %. Paracetamol slightly but significantly increases blood pressure and heart rate. A 2022 double-blind, placebo-controlled, crossover study has provided evidence that daily, high-dose use (4 g per day) of paracetamol increases systolic BP. A review of available research has suggested that increase in systolic blood pressure and increased risk of gastrointestinal bleeding associated with chronic paracetamol use shows
3240-408: Is at higher risk of miscarriage , low birth weight , and premature birth . Children and older individuals are at a risk of developing complications from dengue fever compared to other age groups; young children typically suffer from more intense symptoms. Concurrent infections with tropical diseases like Zika virus can worsen symptoms and make recovery more challenging. Dengue virus (DENV)
3360-905: Is believed to be a novel drug working through two (and possibly three) different modes of action in the fashion of both a traditional opioid and as an SNRI. The effects of serotonin and norepinephrine on pain, while not completely understood, have had causal links established and drugs in the SNRI class are commonly used in conjunction with opioids (especially tapentadol and tramadol) with greater success in pain relief. Dosing of all opioids may be limited by opioid toxicity (confusion, respiratory depression, myoclonic jerks and pinpoint pupils), seizures ( tramadol ), but opioid-tolerant individuals usually have higher dose ceilings than patients without tolerance. Opioids, while very effective analgesics, may have some unpleasant side-effects. Patients starting morphine may experience nausea and vomiting (generally relieved by
3480-462: Is called severe dengue (formerly called dengue hemorrhagic fever or dengue shock syndrome ). Severe dengue can lead to shock, internal bleeding, organ failure and even death. Warning signs include severe stomach pain, vomiting, difficulty breathing, and blood in the nose, gums, vomit or stools. During this period, there is leakage of plasma from the blood vessels, together with a reduction in platelets . This may result in fluid accumulation in
3600-452: Is converted to sulfate by sulfation enzymes SULT1A1 , SULT1A3 , and SULT1E1 . A minor metabolic pathway (5–15 %) of oxidation by cytochrome P450 enzymes, mainly by CYP2E1 , forms a toxic metabolite known as NAPQI ( N -acetyl- p -benzoquinone imine). NAPQI is responsible for the liver toxicity of paracetamol. At usual doses of paracetamol, NAPQI is quickly detoxified by conjugation with glutathione . The non-toxic conjugate APAP-GSH
3720-427: Is divided into three phases: febrile, critical, and recovery. The febrile phase involves high fever (40 °C/104 °F), and is associated with generalized pain and a headache; this usually lasts two to seven days. There may also be nausea, vomiting, a rash, and pains in the muscle and joints. Most people recover within a week or so. In about 5% of cases, symptoms worsen and can become life-threatening. This
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3840-459: Is dose-dependent: it increases from 63 % for 500 mg dose to 89 % for 1000 mg dose. Its plasma terminal elimination half-life is 1.9–2.5 hours, and volume of distribution is roughly 50 L. Protein binding is negligible, except under the conditions of overdose, when it may reach 15–21 %. The concentration in serum after a typical dose of paracetamol usually peaks below 30 μg/mL (200 μmol/L). After 4 hours,
3960-503: Is due to its quinone metabolite NAPQI and NAC also helps in neutralizing it. Kidney failure is also a possible side effect. Prokinetic agents such as metoclopramide accelerate gastric emptying, shorten time (t max ) to paracetamol peak blood plasma concentration (C max ), and increase C max . Medications slowing gastric emptying such as propantheline and morphine lengthen t max and decrease C max . The interaction with morphine may result in patients failing to achieve
4080-412: Is endemic have only one serotype of the virus in circulation. The disease is said to be hyperendemic in areas where more than one serotype is circulating; this increases the risk of severe disease on a second or subsequent infection. Infections are most commonly acquired in urban environments where the virus is primarily transmitted by the mosquito species Aedes aegypti . This species has adapted to
4200-513: Is evidence suggesting that cannabis can be used to treat chronic pain and muscle spasms , with some trials indicating improved relief of neuropathic pain over opioids. Analgesics are frequently used in combination, such as the paracetamol and codeine preparations found in many non-prescription pain relievers. They can also be found in combination with vasoconstrictor drugs such as pseudoephedrine for sinus -related preparations, or with antihistamine drugs for people with allergies. While
4320-795: Is given subcutaneously as three doses at six month intervals. Qdenga (formerly TAK-003) completed clinical trials in 2022 and was approved for use in the European Union in December 2022; it has been approved by a number of other countries including Indonesia and Brazil, and has been recommended by the SAGE committee of the World Health Organization. It is indicated for the prevention of dengue disease in individuals four years of age and older, and can be administered to people who have not been previously infected with dengue. It
4440-411: Is high population density, poor sanitation, and standing water where mosquitoes can breed. It can be mitigated by taking steps to avoid bites such as by wearing clothing that fully covers the skin, using mosquito netting while resting, and/or the application of insect repellent ( DEET being the most effective). Chronic diseases – such as asthma, sickle cell anemia, and diabetes mellitus – increase
4560-426: Is lacking. Paracetamol is effective for acute migraine: 39 % of people experience pain relief at one hour compared with 20 % in the control group. The aspirin/paracetamol/caffeine combination also "has strong evidence of effectiveness and can be used as a first-line treatment for migraine". Paracetamol on its own only slightly alleviates episodic tension headache in those who have them frequently. However,
4680-487: Is no specific antiviral treatment available for dengue fever. Most cases of dengue fever have mild symptoms, and recovery takes place in a few days. No treatment is required for these cases. Acetaminophen (Paracetamol, Tylenol ) may be used to relieve mild fever or pain. Other common pain relievers, including aspirin , ibuprofen (Advil, Motrin IB, others) and naproxen sodium (Aleve) should be avoided as they can increase
4800-517: Is not a blood thinner (and thus may be used in patients where bleeding is a concern), and it does not cause gastric irritation. Compared to Ibuprofen—which can have adverse effects that include diarrhea, vomiting, and abdominal pain—paracetamol is well tolerated with fewer side effects. Prolonged daily use may cause kidney or liver damage.Paracetamol is metabolized by the liver and is hepatotoxic ; side effects may be more likely in chronic alcoholics or patients with liver damage. Until 2010 paracetamol
4920-601: Is not addictive, and tolerance usually does not develop. However, tolerance may develop in some cases. Ziconotide , a blocker of potent N-type voltage-gated calcium channels , is administered intrathecally for the relief of severe, usually cancer-related pain. Certain drugs that have been introduced for uses other than analgesics are also used in pain management. Both first-generation (such as amitriptyline ) and newer antidepressants (such as duloxetine ) are used alongside NSAIDs and opioids for pain involving nerve damage and similar problems. Other agents directly potentiate
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5040-448: Is not fully understood. It appears that ADE occurs when the antibodies generated during an immune response recognize and bind to a pathogen, but they fail to neutralize it. Instead, the antibody-virus complex has an enhanced ability to bind to the Fcγ receptors of the target immune cells, enabling the virus to infect the cell and reproduce itself. When a dengue virus carrying mosquito bites
5160-677: Is not recommended; however, doses may be alternated if required. Paracetamol is used for the relief of mild to moderate pain such as headache, muscle aches, minor arthritis pain, toothache as well as pain caused by cold, flu, sprains, and dysmenorrhea . It is recommended, in particular, for acute mild to moderate pain, since the evidence for the treatment of chronic pain is insufficient. The benefits of paracetamol in musculoskeletal conditions, such as osteoarthritis and backache, are uncertain. It appears to provide only small and not clinically important benefits in osteoarthritis . American College of Rheumatology and Arthritis Foundation guideline for
5280-515: Is not thought to be effective. Reducing open collections of water through environmental modification is the preferred method of control, given the concerns of negative health effects from insecticides and greater logistical difficulties with control agents. Ideally, mosquito control would be a community activity, e.g. when all members of a community clear blocked gutters and street drains and keep their yards free of containers with standing water. If residences have direct water connections this eliminates
5400-441: Is nothing like that of ibuprofen. Increase in risk-taking behavior is possible. According to the U.S. Food and Drug Administration (FDA), the drug may cause rare and possibly fatal skin reactions such as Stevens–Johnson syndrome and toxic epidermal necrolysis , Rechallenge tests and an analysis of American but not French pharmacovigilance databases indicated a risk of these reactions. In clinical trials for osteoarthritis ,
5520-422: Is only recommended to prevent re-infection in individuals who have been previously infected. The second vaccine, Qdenga, became available in 2022 and is suitable for adults, adolescents and children from four years of age. The earliest descriptions of a dengue outbreak date from 1779; its viral cause and spread were understood by the early 20th century. Already endemic in more than one hundred countries, dengue
5640-458: Is reduced to 4-aminophenol by hydrogenation over Raney nickel . In another method, nitrobenzene is reduced electrolytically giving 4-aminophenol directly. Additionally, 4-nitrophenol can be selectively reduced by Tin(II) Chloride in absolute ethanol or ethyl acetate to produce a 91 % yield of 4-aminophenol. An alternative industrial synthesis developed at Celanese involves firstly direct acylation of phenol with acetic anhydride in
5760-428: Is safe for children, as paracetamol is not associated with a risk of Reye's syndrome in children with viral illnesses. Chronic users of paracetamol may have a higher risk of developing blood cancer . Paracetamol safety in pregnancy has been under increased scrutiny. There appears to be no link between paracetamol use in the first trimester and adverse pregnancy outcomes or birth defects . However, indications exist of
5880-712: Is spreading from tropical and subtropical regions to the Iberian Peninsula and the southern states of the US, partly attributed to climate change. It is classified as a neglected tropical disease . During 2023, more than 5 million infections were reported, with more than 5,000 dengue-related deaths. As most cases are asymptomatic or mild, the actual numbers of dengue cases and deaths are under-reported. Typically, people infected with dengue virus are asymptomatic (80%) or have only mild symptoms such as an uncomplicated fever. Others have more severe illness (5%), and in
6000-400: Is superior to either drug alone. The pain relief paracetamol provides in osteoarthritis is small and clinically insignificant. The evidence in its favor for the use in low back pain, cancer pain , and neuropathic pain is insufficient. In the short term, paracetamol is safe and effective when used as directed. Short term adverse effects are uncommon and similar to ibuprofen, but paracetamol
6120-450: Is supportive and includes giving fluid either by mouth or intravenously . Dengue is spread by several species of female mosquitoes of the Aedes genus , principally Aedes aegypti . Infection can be prevented by mosquito elimination and the prevention of bites. Two types of dengue vaccine have been approved and are commercially available. Dengvaxia became available in 2016 but it
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#17327979695826240-439: Is taken up in the bile and further degraded to mercapturic and cysteine conjugates that are excreted in the urine. In overdose, glutathione is depleted by the large amount of formed NAPQI, and NAPQI binds to mitochondria proteins of the liver cells causing oxidative stress and toxicity. Yet another minor but important direction of metabolism is deacetylation of 1–2 % of paracetamol to form p -aminophenol . p -Aminophenol
6360-453: Is the foremost cause of acute liver failure in the Western world , and accounts for most drug overdoses in the United States, the United Kingdom, Australia, and New Zealand. Paracetamol was first made in 1878 by Harmon Northrop Morse or possibly in 1852 by Charles Frédéric Gerhardt . It is the most commonly used medication for pain and fever in both the United States and Europe. It is on
6480-442: Is then converted in the brain by fatty acid amide hydrolase into AM404 , a compound that may be partially responsible for the analgesic action of paracetamol. The classical methods for the production of paracetamol involve the acetylation of 4-aminophenol with acetic anhydride as the last step. They differ in how 4-aminophenol is prepared. In one method, nitration of phenol with nitric acid affords 4-nitrophenol , which
6600-498: Is typically safer than nonsteroidal anti-inflammatory drugs (NSAIDs) for long-term use. Paracetamol is also often used in patients who cannot tolerate NSAIDs like ibuprofen. Chronic consumption of paracetamol may result in a drop in hemoglobin level, indicating possible gastrointestinal bleeding , and abnormal liver function tests . The recommended maximum daily dose for an adult is three to four grams. Higher doses may lead to toxicity, including liver failure . Paracetamol poisoning
6720-462: Is unclear. Paracetamol should not be used solely with the aim of reducing body temperature; however, it may be considered for children with fever who appear distressed. It does not prevent febrile seizures . It appears that 0.2 °C decrease of the body temperature in children after a standard dose of paracetamol is of questionable value, particularly in emergency situations. Based on this, some physicians advocate using higher doses that may decrease
6840-490: Is used to treat neuropathic pain. Similarly, the gabapentinoids gabapentin and pregabalin are prescribed for neuropathic pain, and phenibut is available without prescription. Gabapentinoids work as α 2 δ-subunit blockers of voltage-gated calcium channels , and tend to have other mechanisms of action as well. Gabapentinoids are all anticonvulsants , which are most commonly used for neuropathic pain, as their mechanism of action tends to inhibit pain sensation originating from
6960-570: The World Health Organization's List of Essential Medicines . Paracetamol is available as a generic medication , with brand names including Tylenol and Panadol among others . In 2022, it was the 114th most commonly prescribed medication in the United States, with more than 5 million prescriptions. Paracetamol is used for reducing fever. However, there has been a lack of research on its antipyretic properties, particularly in adults, and thus its benefits are unclear. As
7080-463: The chest and abdominal cavity as well as depletion of fluid from the circulation and decreased blood supply to vital organs . The recovery phase usually lasts two to three days. The improvement is often striking, and can be accompanied with severe itching and a slow heart rate . Complications following severe dengue include fatigue, somnolence, headache, concentration impairment and memory impairment. A pregnant woman who develops dengue
7200-461: The 15th to 19th centuries due to the slave trade and consequent expansion of international trading. There have been descriptions of epidemics of dengue-like illness in the 17th century, and it is likely that epidemics in Jakarta , Cairo , and Philadelphia during the 18th century were caused by dengue. It is assumed that dengue was constantly present in many tropical urban centres throughout
7320-483: The 19th and early 20th centuries, even though significant outbreaks were infrequent. The marked spread of dengue during and after the Second World War has been attributed partly to disruption caused by the war, and partly to subsequent urbanisation in south-east Asia. As novel serotypes were introduced to regions already endemic with dengue, outbreaks of severe disease followed. The severe hemorrhagic form of
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#17327979695827440-434: The 20th century. Analgesics are typically classified based on their mechanism of action. Paracetamol, also known as acetaminophen or APAP, is a medication used to treat pain and fever . It is typically used for mild to moderate pain. In combination with opioid pain medication , paracetamol is now used for more severe pain such as cancer pain and after surgery. It is typically used either by mouth or rectally but
7560-539: The COX2 enzyme (traditional NSAIDs block both versions in general). These drugs (such as rofecoxib , celecoxib , and etoricoxib ) are equally effective analgesics when compared with NSAIDs, but cause less gastrointestinal hemorrhage in particular. After widespread adoption of the COX-2 inhibitors, it was discovered that most of the drugs in this class increase the risk of cardiovascular events by 40% on average. This led to
7680-437: The U.S. than overdose of any other pharmacological substance. According to the FDA, in the United States, "56,000 emergency room visits, 26,000 hospitalizations, and 458 deaths per year [were] related to acetaminophen-associated overdoses during the 1990s. Within these estimates, unintentional acetaminophen overdose accounted for nearly 25 % of the emergency department visits, 10 % of the hospitalizations, and 25 % of
7800-603: The US was identified in California. The disease infects all races, sexes, and ages equally. In endemic areas, the infection is most commonly seen in children who then acquire a lifelong partial immunity. The first historical record of a case of probable dengue fever is in a Chinese medical encyclopedia from the Jin dynasty (266–420) which referred to a "water poison" associated with flying insects. The principal mosquito vector of dengue, Aedes aegypti , spread out of Africa in
7920-419: The action of opioids when used against pain, especially of neuropathic origin. Dextromethorphan has been noted to slow the development of and reverse tolerance to opioids, as well as to exert additional analgesia by acting upon NMDA receptors, as does ketamine . Some analgesics such as methadone and ketobemidone and perhaps piritramide have intrinsic NMDA action. The anticonvulsant carbamazepine
8040-409: The active form of COX-1 and COX-2 enzymes. This occurs only when the concentration of arachidonic acid and peroxides is low. Under these conditions, COX-2 is the predominant form of cyclooxygenase, which explains the apparent COX-2 selectivity of paracetamol. Under the conditions of inflammation, the concentration of peroxides is high, which counteracts the reducing effect of paracetamol. Accordingly,
8160-528: The activity of the primary excitatory (signal boosting) neurotransmitter , glutamate. It also functions as an analgesic to a lesser degree by increasing the activity of the primary inhibitory (signal reducing) neurotransmitter, GABA. Attempting to use alcohol to treat pain has also been observed to lead to negative outcomes including excessive drinking and alcohol use disorder . Medical cannabis , or medical marijuana , refers to cannabis or its cannabinoids used to treat disease or improve symptoms. There
8280-458: The analgesic effect of paracetamol. In 2018, Suemaru et al . found that, in mice, paracetamol exerts an anticonvulsant effect by activation of the TRPV1 receptors and a decrease in neuronal excitability by hyperpolarization of neurons. The exact mechanism of the anticonvulsant effect of acetaminophen is not clear. According to Suemaru et al ., acetaminophen and its active metabolite AM404 show
8400-431: The anti-inflammatory action of paracetamol is slight. The anti-inflammatory action of paracetamol (via COX inhibition) has also been found to primarily target the central nervous system and not peripheral areas of the body, explaining the lack of side effects associated with conventional NSAIDs such as gastric bleeding. The second mechanism centers on the paracetamol metabolite AM404 . This metabolite has been detected in
8520-498: The aspirin/paracetamol/caffeine combination is superior to both paracetamol alone and placebo and offers meaningful relief of tension headache: two hours after administering the medication, 29 % of those who took the combination were pain-free as compared with 21 % on paracetamol and 18 % on placebo. The German, Austrian, and Swiss headache societies and the German Society of Neurology recommend this combination as
8640-426: The benefits of its use for fever are unclear, particularly in the context of fever of viral origins. The aspirin/paracetamol/caffeine combination also helps with both conditions where the pain is mild and is recommended as a first-line treatment for them. Paracetamol is effective for post- surgical pain, but it is inferior to ibuprofen. The paracetamol/ibuprofen combination provides further increase in potency and
8760-427: The blood pressure becomes so low that it cannot supply sufficient blood to vital organs. The spread of the virus to the bone marrow leads to reduced numbers of platelets, which are necessary for effective blood clotting; this increases the risk of bleeding, the other major complication of dengue fever. The principal risk for infection with dengue is the bite of an infected mosquito. This is more probable in areas where
8880-451: The body's becoming used to the drug (tolerance) can occur. The effect of tolerance means that frequent use of the drug may result in its diminished effect. When safe to do so, the dosage may need to be increased to maintain effectiveness against tolerance, which may be of particular concern regarding patients with chronic pain and requiring an analgesic over long periods. Opioid tolerance is often addressed with opioid rotation therapy in which
9000-462: The brains of animals and cerebrospinal fluid of humans taking paracetamol. It is formed in the brain from another paracetamol metabolite 4-aminophenol by action of fatty acid amide hydrolase . AM404 is a weak agonist of cannabinoid receptors CB1 and CB2 , an inhibitor of endocannabinoid transporter , and a potent activator of TRPV1 receptor. This and other research indicate that the endocannabinoid system and TRPV1 may play an important role in
9120-502: The concentration is usually less than 10 μg/mL (66 μmol/L). Paracetamol is metabolized primarily in the liver, mainly by glucuronidation and sulfation , and the products are then eliminated in the urine (see the Scheme on the right). Only 2–5 % of the drug is excreted unchanged in the urine. Glucuronidation by UGT1A1 and UGT1A6 accounts for 50–70 % of the drug metabolism. Additional 25–35 % of paracetamol
9240-406: The counter in most countries, whereas various others are prescription drugs owing to the substantial risks and high chances of overdose , misuse , and addiction in the absence of medical supervision. The word analgesic derives from Greek an- ( ἀν- , "without"), álgos ( ἄλγος , "pain"), and -ikos ( -ικος , forming adjectives ). Such drugs were usually known as " anodynes " before
9360-498: The counter in most countries. These drugs have been derived from NSAIDs. The cyclooxygenase enzyme inhibited by NSAIDs was discovered to have at least two different versions: COX1 and COX2. Research suggested most of the adverse effects of NSAIDs to be mediated by blocking the COX1 ( constitutive ) enzyme, with the analgesic effects being mediated by the COX2 ( inducible ) enzyme. Thus, the COX2 inhibitors were developed to inhibit only
9480-756: The deaths." Overdoses are frequently related to high-dose recreational use of prescription opioids , as these opioids are most often combined with paracetamol. The overdose risk may be heightened by frequent consumption of alcohol. Untreated paracetamol overdose results in a lengthy, painful illness. Signs and symptoms of paracetamol toxicity may initially be absent or non-specific symptoms . The first symptoms of overdose usually begin several hours after ingestion, with nausea , vomiting , sweating, and pain as acute liver failure starts. People who take overdoses of paracetamol do not fall asleep or lose consciousness, although most people who attempt suicide with paracetamol wrongly believe that they will be rendered unconscious by
9600-417: The disease develops into severe dengue (previously known as dengue hemorrhagic fever or dengue shock syndrome) with bleeding , low levels of blood platelets , blood plasma leakage, and dangerously low blood pressure . Dengue virus has four confirmed serotypes ; infection with one type usually gives lifelong immunity to that type, but only short-term immunity to the others. Subsequent infection with
9720-442: The disease include A. albopictus , A. polynesiensis and A. scutellaris . Humans are the primary host of the virus, but it also circulates in nonhuman primates , and can infect other mammals. An infection can be acquired via a single bite. For 2 to 10 days after becoming newly infected, a person's bloodstream will contain a high level of virus particles (the viremic period). A female mosquito that takes
9840-457: The disease is endemic, especially where there is high population density, poor sanitation, and standing water where mosquitoes can breed. It can be mitigated by taking steps to avoid bites such as by wearing clothing that fully covers the skin, using mosquito netting while resting, and/or the application of insect repellent (DEET being the most effective); it is also advisable to treat clothing, nets and tents with 0.5% permethrin . Protection of
9960-664: The disease was first reported in the Philippines in 1953; by the 1970s, it had become recognised as a major cause of child mortality in Southeast Asia. In Central and South America, the Aedes mosquito had been eradicated in the 1950s; however the eradication program was discontinued in the 1970s and the disease re-established itself in the region during the 1980s, becoming hyperendemic and causing significant epidemics. Dengue has continued to increase in prevalence during
10080-418: The drug. Treatment is aimed at removing the paracetamol from the body and replenishing glutathione . Activated charcoal can be used to decrease absorption of paracetamol if the person comes to the hospital soon after the overdose. While the antidote, acetylcysteine (also called N -acetylcysteine or NAC), acts as a precursor for glutathione, helping the body regenerate enough to prevent or at least decrease
10200-556: The effects of analgesics, such as using hydroxyzine , promethazine , carisoprodol , or tripelennamine to increase the pain-killing ability of a given dose of opioid analgesic. Adjuvant analgesics, also called atypical analgesics, include orphenadrine , mexiletine , pregabalin , gabapentin , cyclobenzaprine , hyoscine (scopolamine), and other drugs possessing anticonvulsant, anticholinergic, and/or antispasmodic properties, as well as many other drugs with CNS actions. These drugs are used along with analgesics to modulate and/or modify
10320-579: The exception of Antarctica. The Americas, Southeast Asia and the Western Pacific regions are the most seriously affected. It is difficult to estimate the full extent of the disease, as many cases are mild and not correctly diagnosed. WHO currently estimates that 3.9 billion people are at risk of dengue infection. In 2013, it was estimated that 390 million dengue infections occur every year, with 500,000 of these developing severe symptoms and 25,000 deaths. Generally, areas where dengue
10440-569: The home can be achieved with door and window screens, by using air conditioning, and by regularly emptying and cleaning all receptacles both indoors and outdoors which may accumulate water (such as buckets, planters, pools or trashcans). The primary method of controlling A. aegypti is by eliminating its habitats . This is done by eliminating open sources of water, or if this is not possible, by adding insecticides or biological control agents to these areas. Generalized spraying with organophosphate or pyrethroid insecticides, while sometimes done,
10560-430: The inhibition of cyclooxygenase (COX) and actions of its metabolite N-arachidonoylphenolamine (AM404). Supporting the first mechanism, pharmacologically and in its side effects, paracetamol is close to classical nonsteroidal anti-inflammatory drugs (NSAIDs) that act by inhibiting COX-1 and COX-2 enzymes and especially similar to selective COX-2 inhibitors . Paracetamol inhibits prostaglandin synthesis by reducing
10680-523: The lowest effective dosage and for the shortest time. In pregnancy, paracetamol and metoclopramide are deemed safe as are NSAIDs until the third trimester . Overdose of paracetamol is caused by taking more than the recommended maximum daily dose of paracetamol for healthy adults (three or four grams), and can cause potentially fatal liver damage . A single dose should not exceed 1000 mg, doses should be taken no sooner than four hours apart, and no more than four doses (4000 mg) in 24 hours. While
10800-415: The management of osteoarthritis notes that the effect size in clinical trials of paracetamol has been very small, which suggests that for most individuals it is ineffective. The guideline conditionally recommends paracetamol for short-term and episodic use to those who do not tolerate nonsteroidal anti-inflammatory drugs. For people taking it regularly, monitoring for liver toxicity is required. Essentially
10920-406: The mosquito, which remains infected for life. Dengue can also be transmitted via infected blood products and through organ donation . Vertical transmission (from mother to child) during pregnancy or at birth has been reported. The principal risk for infection with dengue is the bite of an infected mosquito. This is more probable in areas where the disease is endemic, especially where there
11040-440: The multiple (and often non-acting) components of these combinations. There is some evidence that some treatments using alternative medicine can relieve some types of pain more effectively than placebo . The available research concludes that more research would be necessary to better understand the use of alternative medicine. Nefopam —a monoamine reuptake inhibitor, and calcium and sodium channel modulator—is also approved for
11160-697: The need for wells or street pumps and water-carrying containers. As of March 2024, there are two vaccines to protect against dengue infection; Dengvaxia and Qdenga. Dengvaxia (formerly CYD-TDV) became available in 2015, and is approved for use in the US, EU and in some Asian and Latin American countries. It is an attenuated virus, is suitable for individuals aged 6–45 years and protects against all four serotypes of dengue. Due to safety concerns about antibody-dependent enhancement (ADE), it should only be given to individuals who have previously been infected with dengue, in order to protect them from reinfection. It
11280-443: The nervous system. Topical analgesia is generally recommended to avoid systemic side-effects. Painful joints, for example, may be treated with an ibuprofen - or diclofenac -containing gel (The labeling for topical diclofenac has been updated to warn about drug-induced hepatotoxicity. ); capsaicin also is used topically . Lidocaine , an anesthetic , and steroids may be injected into joints for longer-term pain relief. Lidocaine
11400-449: The number of participants reporting adverse effects was similar for those on paracetamol and on placebo. However, the abnormal liver function tests (meaning there was some inflammation or damage to the liver) were almost four times more likely in those on paracetamol, although the clinical importance of this effect is uncertain. After 13 weeks of paracetamol therapy for knee pain, a drop in hemoglobin level indicating gastrointestinal bleeding
11520-597: The other hand, the anti-tuberculosis drug isoniazid cuts the formation of NAPQI by 70%. Ranitidine increased paracetamol area under the curve (AUC) 1.6-fold. AUC increases are also observed with nizatidine and cisapride . The effect is explained by these drugs inhibiting glucuronidation of paracetamol. Paracetamol raises plasma concentrations of ethinylestradiol by 22 % by inhibiting its sulfation. Paracetamol increases INR during warfarin therapy and should be limited to no more than 2 g per week. Paracetamol appears to exert its effects through two mechanisms:
11640-559: The outcome in febrile patients with stroke. The results are contradictory for paracetamol use in sepsis: higher mortality, lower mortality, and no change in mortality were all reported. Paracetamol offered no benefit in the treatment of dengue fever and was accompanied by a higher rate of liver enzyme elevation: a sign of a potential liver damage. Overall, there is no support for a routine administration of antipyretic drugs, including paracetamol, to hospitalized patients with fever and infection. The efficacy of paracetamol in children with fever
11760-432: The paracetamol/codeine combination to be more effective than paracetamol alone: it provided significant pain relief to as much as 53 % of the participants, while the placebo helped only 7 %. Paracetamol fails to relieve procedural pain in newborn babies . For perineal pain postpartum paracetamol appears to be less effective than nonsteroidal anti-inflammatory drugs (NSAIDs). The studies to support or refute
11880-523: The paracetamol/codeine combination which is frequently prescribed for dental pain. The combinations of paracetamol and NSAIDs ibuprofen or diclofenac are promising, possibly offering better pain control than either paracetamol or the NSAID alone. Additionally, the paracetamol/ibuprofen combination may be superior to paracetamol/codeine and ibuprofen/codeine combinations. A meta-analysis of general post-surgical pain, which included dental and other surgery, showed
12000-456: The peak plasma concentration of paracetamol was reached after 20 minutes when fasting versus 90 minutes when fed. High carbohydrate (but not high protein or high fat) food decreases paracetamol peak plasma concentration by four times. Even in the fasting state, the rate of absorption of paracetamol is variable and depends on the formulation, with maximum plasma concentration being reached after 20 minutes to 1.5 hours. Paracetamol's bioavailability
12120-500: The possible damage to the liver; a liver transplant is often required if damage to the liver becomes severe. NAC was usually given following a treatment nomogram (one for people with risk factors, and one for those without), but the use of the nomogram is no longer recommended as evidence to support the use of risk factors was poor and inconsistent, and many of the risk factors are imprecise and difficult to determine with sufficient certainty in clinical practice. Toxicity of paracetamol
12240-467: The presence of hydrogen fluoride to a ketone, then the conversion of the ketone with hydroxylamine to a ketoxime , and finally the acid-catalyzed Beckmann rearrangement of the cetoxime to the para-acetylaminophenol product. 4 -Aminophenol may be obtained by the amide hydrolysis of paracetamol. This reaction is also used to determine paracetamol in urine samples: After hydrolysis with hydrochloric acid, 4 -aminophenol reacts in ammonia solution with
12360-677: The risk of bleeding complications. For moderate illness, those who can drink, are passing urine, have no warning signs and are otherwise reasonably healthy can be monitored carefully at home. Supportive care with analgesics, fluid replacement, and bed rest are recommended. Severe dengue is a life-threatening emergency, requiring hospitalization and potentially intensive care. Warning signs include dehydration , decreasing platelets and increasing hematocrit . Treatment modes include intravenous fluids, and transfusion with platelets or plasma. Most people with dengue recover without any ongoing problems. The risk of death among those with severe dengue
12480-470: The risk of developing a severe form of the disease. Other risk factors for severe disease include female sex, and high body mass index , Infection with one serotype is thought to produce lifelong immunity to that type, but only short-term protection against the other three. Subsequent re-infection with a different serotype increases the risk of severe complications due to phenomenon known as antibody-dependent enhancement (ADE). The exact mechanism of ADE
12600-561: The robust designs of the studies provide a strong evidence in favor of paracetamol causing the increased risk of these neurodevelopmental disorders. In animal experiments, paracetamol disrupts fetal testosterone production, and several epidemiological studies linked cryptorchidism with mother's paracetamol use for more than two weeks in the second trimester. On the other hand, several studies did not find any association. The consensus recommendation appears to be to avoid prolonged use of paracetamol in pregnancy and use it only when necessary, at
12720-620: The same mode of transmission ( Aedes mosquitoes) and are often endemic in the same regions, so that it is possible to be infected simultaneously by more than one disease. For travellers, dengue fever diagnosis should be considered in anyone who develops a fever within two weeks of being in the tropics or subtropics . Warning symptoms of severe dengue include abdominal pain, persistent vomiting, odema, bleeding, lethargy, and liver enlargement. Once again, these symptoms can be confused with other diseases such as malaria, gastroenteritis, leptospirosis, and typhus. Blood tests can be used to confirm
12840-455: The same recommendation was issued by EULAR for hand osteoarthritis. Similarly, the ESCEO algorithm for the treatment of knee osteoarthritis recommends limiting the use of paracetamol to short-term rescue analgesia only. Paracetamol is ineffective for acute low back pain. No randomized clinical trials evaluated its use for chronic or radicular back pain, and the evidence in favor of paracetamol
12960-416: The sensation of pain ( hyperalgesia ) and can even make non-painful stimuli painful ( allodynia ). Alcohol has biological, mental, and social effects which influence the consequences of using alcohol for pain. Moderate use of alcohol can lessen certain types of pain in certain circumstances. The majority of its analgesic effects come from antagonizing NMDA receptors, similarly to ketamine, thus decreasing
13080-417: The symptoms, such as the fever, the flu-like symptoms, and the severe pains. In severe infection, the virus production inside the body is greatly increased, and many more organs (such as the liver and the bone marrow ) can be affected. Fluid from the bloodstream leaks through the wall of small blood vessels into body cavities due to increased capillary permeability . As a result, blood volume decreases, and
13200-412: The temperature by as much as 0.7 °C. Meta-analyses showed that paracetamol is less effective than ibuprofen in children (marginally less effective, according to another analysis), including children younger than 2 years old, with equivalent safety. Exacerbation of asthma occurs with similar frequency for both medications. Giving paracetamol and ibuprofen together at the same time to children under 5
13320-548: The therapeutic concentration of paracetamol; the clinical significance of interactions with metoclopramide and propantheline is unclear. There have been suspicions that cytochrome inducers may enhance the toxic pathway of paracetamol metabolism to NAPQI (see Paracetamol#Pharmacokinetics ). By and large, these suspicions have not been confirmed. Out of the inducers studied, the evidence of potentially increased liver toxicity in paracetamol overdose exists for phenobarbital , primidone , isoniazid , and possibly St John's wort . On
13440-475: The treatment of moderate to severe pain in some countries. Flupirtine is a centrally acting K channel opener with weak NMDA antagonist properties. It was used in Europe for moderate to strong pain, as well as its migraine -treating and muscle-relaxant properties. It has no significant anticholinergic properties, and is believed to be devoid of any activity on dopamine, serotonin, or histamine receptors. It
13560-641: The urban environment, is generally found close to human habitation, prefers humans as its host, and takes advantage of small bodies of standing water (such as tanks and buckets) in which to breed. In rural settings the virus is transmitted to humans by A. aegypti and other related mosquitoes such as Aedes albopictus . Both these species have expanding ranges. There are two subspecies of Aedes aegypti , where Aedes aegypti formosus can be found in natural habitats such as forests and Aedes Aegypti aegypti has adapted to urban domestic habitats. Dengue has increased in incidence in recent decades, with WHO recording
13680-743: The use of paracetamol for cancer pain and for neuropathic pain are lacking. There is limited evidence in favor of the use of the intravenous form of paracetamol for acute pain control in the emergency department. The combination of paracetamol with caffeine is superior to paracetamol alone for the treatment of acute pain. Paracetamol helps ductal closure in patent ductus arteriosus . It is as effective for this purpose as ibuprofen or indomethacin , but results in less frequent gastrointestinal bleeding than ibuprofen. Its use for extremely low birth weight and gestational age infants however requires further study. Gastrointestinal adverse effects such as nausea and abdominal pain are extremely uncommon, and their frequency
13800-570: The use of paracetamol, aspirin, ibuprofen , naproxen , and other NSAIDS concurrently with weak to mid-range opiates (up to about the hydrocodone level) has been said to show beneficial synergistic effects by combating pain at multiple sites of action, several combination analgesic products have been shown to have few efficacy benefits when compared to similar doses of their individual components. Moreover, these combination analgesics can often result in significant adverse events, including accidental overdoses, most often due to confusion that arises from
13920-478: The virus. There are four confirmed strains of the virus, called serotypes , referred to as DENV-1, DENV-2, DENV-3 and DENV-4. The distinctions between the serotypes are based on their antigenicity . Dengue virus is most frequently transmitted by the bite of mosquitos in the Aedes genus, particularly A. aegypti . They prefer to feed at dusk and dawn, but they may bite and thus spread infection at any time of day. Other Aedes species that may transmit
14040-410: The withdrawal of rofecoxib and valdecoxib, and warnings on others. Etoricoxib seems relatively safe, with the risk of thrombotic events similar to that of non-coxib NSAID diclofenac. Morphine , the archetypal opioid , and other opioids (e.g., codeine , oxycodone , hydrocodone , dihydromorphine , pethidine ) all exert a similar influence on the cerebral opioid receptor system. Buprenorphine
14160-404: Was also associated with a 20–30 % increase in autism spectrum disorder , attention deficit hyperactivity disorder , and conduct disorder , with the association being lower in a meta-analysis where a larger demographic was used, but it is unclear whether this is a causal relationship and there was potential bias in the findings. There is also an argument that the large number, consistency, and
14280-482: Was believed safe in pregnancy however, in a study published in October 2010 it has been linked to infertility in the adult life of the unborn. Like NSAIDs and unlike opioid analgesics, paracetamol has not been found to cause euphoria or alter mood. One recent research study has showed some evidence that paracetamol can ease psychological pain, but more studies are needed to draw an informed conclusion. Unlike aspirin, it
14400-487: Was observed in 20 % of participants, this rate being similar to the ibuprofen group. Due to the absence of controlled studies , most of the information about the long-term safety of paracetamol comes from observational studies . These indicate a consistent pattern of increased mortality as well as cardiovascular ( stroke , myocardial infarction ), gastrointestinal ( ulcers , bleeding ) and renal adverse effects with increased dose of paracetamol. Use of paracetamol
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