The program was started after  Robert C. Randall   brought a lawsuit ( Randall v. U.S ) [ 13 ]  against the FDA, the  Drug Enforcement Administration , the  National Institute on Drug Abuse , the  Department of Justice , and the  Department of Health, Education & Welfare .  Randall, who had  glaucoma , had successfully used the  Common Law doctrine of necessity  to argue against criminal charges of marijuana cultivation that had been brought against him, because his use of cannabis was deemed a  medical necessity  ( U.S. v. Randall ). [ 13 ]  On November 24, 1976, federal Judge James Washington ruled in his favor. [ 14 ] : 142  [ 15 ]


The settlement in  Randall v. U.S.  became the legal basis for the FDA's compassionate IND program. [ 13 ]   People were only allowed to use cannabis under the program who had certain conditions, like glaucoma, known to be alleviated with cannabis.  The scope was later expanded to include people with  AIDS  in the mid-1980s. At its peak, fifteen people received the drug. 43 people were approved for the program, but 28 of the people whose doctors completed the necessary paperwork never received any cannabis. [ 16 ] [ 14 ]  The program stopped accepting new people in 1992 after public health authorities concluded there was no scientific value to it, and due to President  George H. W. Bush  administration's policies.  As of 2011, four people continued to receive cannabis from the government under the program. [ 17 ]


The closure of the program during the height of the AIDS epidemic led to the formation of the medical cannabis movement in the United States, a movement which initially sought to provide cannabis for treating anorexia and wasting syndrome in people with AIDS. [ 18 ]


In November 2001 the Abigail Alliance for Better Access to Developmental Drugs was established by Frank Burroughs in memory of his daughter, Abigail. [ 19 ]    The Alliance seeks broader availability of investigational drugs on behalf of people with terminal illnesses.  It is best known for a legal case, which it lost,  Abigail Alliance v. von Eschenbach , in which it was represented by the  Washington Legal Foundation . On August 7, 2007, in an 8–2 ruling, the  U.S. Court of Appeals for the District of Columbia Circuit  reversed an earlier ruling in favor of the Alliance. [ 20 ]   In 2008, the  Supreme Court of the United States  declined to hear their appeal. This decision left standing the appellate court decision that people who are terminal ill patients have no legal right to demand "a potentially toxic drug with no proven therapeutic benefit". [ 21 ]


In March 2014, Josh Hardy, a 7-year-old boy from Virginia, made national headlines that sparked a conversation on pediatric access to investigational drugs when his family's request for  brincidofovir  was declined by the drug manufacturer, Chimerix. [ 22 ]  The company reversed its decision after pressure from cancer advocacy organizations, and Josh received the drug that saved his life. [ 23 ] [ 24 ]  Hardy later passed away in September 2016 due to complications related to his underlying cancer diagnosis. [ 25 ]  In 2016 Kids v Cancer, a pediatric cancer advocacy organization, launched the Compassionate Use Navigator to assist physicians and guide families about the application process. [ 26 ]  Since then, FDA simplified the application process, but stressed that it cannot require a manufacturer to provide a product. [ 27 ] [ 28 ]  FDA receives about 1,500 expanded access requests per year and authorizes 99% of it. [ 29 ]


The  first-dose phenomenon  is a sudden and severe fall in  blood pressure  that can occur when changing from a lying to a standing position the first time that an  alpha blocker  drug is used [ 1 ]  or when resuming the drug after many months off. [ 2 ]  This  postural hypotension  usually happens shortly after the first dose is absorbed into the blood and can result in  syncope  (fainting). Syncope occurs in approximately 1% of patients given an initial dose of 2 mg  prazosin  or greater. This adverse effect is self-limiting and in most cases does not recur after the initial period of therapy or during subsequent dose titration. [ 3 ]


The alpha blocker  prazosin  (Minipress) is most notorious for producing a first dose phenomenon. Other drugs of the same family,  doxazosin  (Cardura) and  terazosin  (Hytrin), can also cause this phenomenon, though less frequently.


The cause is not clear. It occurs more commonly in patients who are salt and fluid volume depleted (as happens due to the use of  diuretics ), or were using  beta blockers . [ 4 ]  Diuretics and beta blockers are frequently used to control  hypertension . For this reason, treatment with  prazosin  (Minipress) should always be initiated with a low dose and should be taken at bedtime to avoid standing position.


This effect is also observed after the administration of the first dose of drugs in the ACEi class ( angiotensin-converting enzyme inhibitor ). [ 5 ]  This may occur with the class's better known side effect of dry cough (due to decreased breakdown of bradykinin), though there is no clear relationship between the two side effects.


The first dose phenomenon in ACEi is reduced and made safer by avoiding diuretics for 24 hours prior to first dose, taking first dose at night (so avoiding falls, etc) and starting on low doses and titrating upwards.


Redirect to:


In  pharmacology ,  hazardous drugs  are drugs that are known to cause harm, which may or may not include  genotoxicity  (the ability to cause a change or mutation in genetic material). Genotoxicity might involve  carcinogenicity , the ability to cause  cancer  in animal models, humans or both;  teratogenicity , which is the ability to cause defects on  fetal  development or fetal malformation; and lastly hazardous drugs are known to have the potential to cause fertility impairment, which is a major concern for most clinicians. [ 1 ]  These drugs can be classified as  antineoplastics , cytotoxic agents, biologic agents, antiviral agents and immunosuppressive agents. This is why safe handling of hazardous drugs is crucial.


Safe handling refers to the process in which health care workers adhere to practices set forth by national health and safety organizations, that have been designed to eliminate or significantly reduce occupational exposure. Some of these practices include but are not limited to, donning of personal protective equipment such as a disposable gown, gloves, masks and the utilization of a closed-system drug transfer device. The key safe handling is to protect the health care worker throughout the three phases of contact with the hazardous drugs. These phases are drug preparation, administration and disposal. Some studies have shown that while compounding hazardous drugs in a Class II BSC in conjunction with a closed-system drug transfer device, a  significant decrease in drug contaminants inside a Class II BSC has resulted. [ 2 ]  This led the Oncology Nursing Society (ONS) to make the statement in 2003 that a closed-system drug transfer device is viewed as one of safest measures to prevent hazardous drug exposure in a clinician’s working environment. [ 3 ]  However, a  Cochrane  review published in 2018 that synthesized all available controlled studies found no evidence of a closed-system drug transfer device offering an additional decrease in contamination or exposure to safe handling practices alone. [ 4 ]


It has been determined that current  personal protective equipment  (PPE) does not provide adequate protection against workers handling hazardous drugs - NIOSH states that “... measurable concentrations of some hazardous drugs have been documented in the urine of health care workers who prepared or administered them − even after safety precautions had been employed.” [ 1 ]  Further, NIOSH recommends that institutions should "consider using devices such as closed-system transfer devices. Closed systems limit the potential for generating aerosols and exposing workers". [ 1 ]  Other guidelines outline that "As other products become available, they should meet the definition of a  closed system drug transfer device  established by NIOSH and should be required to demonstrate their effectiveness in independent studies". [ 2 ]


Hormesis  is a two-phased  dose-response relationship  to an environmental agent whereby low-dose amounts have a beneficial effect and high-dose amounts are either inhibitory to function or toxic. [ 1 ] [ 2 ] [ 3 ] [ 4 ]  Within the  hormetic zone , the biological response to low-dose amounts of some  stressors  is generally favorable. An example is the breathing of  oxygen , which is required in low amounts (in air) via  respiration  in living animals, but can be toxic in high amounts, even in a managed clinical setting. [ 5 ]


In  toxicology , hormesis is a dose-response phenomenon to  xenobiotics  or other stressors.
In  physiology  and nutrition, hormesis has regions extending from low-dose deficiencies to  homeostasis, and potential toxicity at high levels. [ 6 ]  Physiological concentrations of an agent above or below homeostasis may adversely affect an organism, where the hormetic zone is a region of homeostasis of balanced nutrition. [ 7 ]  In  pharmacology , the hormetic zone is similar to the  therapeutic window .


In the context of toxicology, the hormesis model of dose response is vigorously debated. [ 8 ]  The biochemical mechanisms by which hormesis works (particularly in applied cases pertaining to behavior and toxins) remain under early laboratory research and are not well understood. [ 6 ]


The term "hormesis" derives from  Greek   hórmēsis  for "rapid motion, eagerness", itself from ancient Greek  hormáein  to excite. [ 4 ]  The same Greek root provides the word  hormone . The term "hormetics" is used for the study of hormesis. [ 6 ]  The word hormesis was first reported in English in 1943. [ 4 ]


A form of hormesis famous in antiquity was  Mithridatism , the practice whereby  Mithridates VI  of  Pontus  supposedly made himself immune to a variety of toxins by regular exposure to small doses.  Mithridate  and  theriac ,  polypharmaceutical   electuaries  claiming descent from his formula and initially including flesh from poisonous animals, were consumed for centuries by emperors, kings, and queens as protection against poison and ill health. In the  Renaissance , the  Swiss  doctor  Paracelsus  said, " All things are poison, and nothing is without poison; the dosage alone makes it so a thing is not a poison. "


German  pharmacologist   Hugo Schulz  first described such a phenomenon in 1888 following his own observations that the growth of yeast could be stimulated by small doses of poisons. This was coupled with the work of German physician  Rudolph Arndt , who studied animals given low doses of drugs, eventually giving rise to the  Arndt–Schulz rule . [ 8 ]  Arndt's advocacy of  homeopathy  contributed to the rule's diminished credibility in the 1920s and 1930s. [ 8 ]  The term "hormesis" was coined and used for the first time in a scientific paper by  Chester M. Southam  and J. Ehrlich in 1943 in the journal  Phytopathology , volume 33, pp. 517–541.


In 2004,  Edward Calabrese  evaluated the concept of hormesis. [ 9 ] [ 10 ]  Over 600 substances show a U-shaped  dose–response relationship ; Calabrese and Baldwin wrote: "One percent (195 out of 20,285) of the published articles contained 668 dose-response relationships that met the entry criteria [of a U-shaped response indicative of hormesis]" [ 11 ]


Carbon monoxide  is produced in small quantities across  phylogenetic  kingdoms, where it has essential roles as a  neurotransmitter  (subcategorized as a  gasotransmitter ). The majority of endogenous carbon monoxide is produced by  heme oxygenase ; the loss of heme oxygenase and subsequent loss of carbon monoxide signaling has catastrophic implications for an organism. [ 12 ]  In addition to physiological roles, small amounts of carbon monoxide can be inhaled or administered in the form of  carbon monoxide-releasing molecules  as a therapeutic agent. [ 13 ]


Regarding the hormetic curve graph:


Many organisms maintain a hormesis relationship with oxygen, which follows a hormetic curve similar to carbon monoxide:


Physical exercise intensity may exhibit a hormetic curve. Individuals with low levels of physical activity are at risk for some diseases; however, individuals engaged in moderate, regular exercise may experience less disease risk. [ 15 ]


The possible effect of small amounts of oxidative stress is under laboratory research. [ 16 ]   Mitochondria  are sometimes described as "cellular power plants" because they generate most of the cell's supply of adenosine triphosphate (ATP), a source of chemical energy.  Reactive oxygen species  (ROS) have been discarded as unwanted byproducts of  oxidative phosphorylation  in mitochondria by the proponents of the free-radical theory of aging promoted by  Denham Harman . The  free-radical theory  states that compounds inactivating ROS would lead to a reduction of oxidative stress and thereby produce an increase in lifespan, although this theory holds only in  basic research . [ 17 ]  However, in over 19  clinical trials , "nutritional and genetic interventions to boost antioxidants have generally failed to increase life span." [ 18 ]


Whether this concept applies to humans remains to be shown, although a 2007  epidemiological  study supports the possibility of mitohormesis, indicating that supplementation with  beta-carotene ,  vitamin A  or  vitamin E  may increase disease  prevalence  in humans. [ 19 ]  More recent studies have reported that  rapamycin  exhibits hormesis, where low doses can enhance cellular longevity by partially inhibiting mTOR, unlike higher doses that are toxic due to complete inhibition. This partial inhibition of  mTOR  (by the hormetic effect of low-dose rapamycin) modulates mTOR–mitochondria  cross-talk , thereby demonstrating mitohormesis; and consequently reducing  oxidative damage , metabolic dysregulation, and  mitochondrial dysfunction , thus slowing cellular  aging . [ 2 ] [ 3 ]


Alcohol  is believed to be hormetic in preventing heart disease and stroke, [ 20 ]  although the benefits of light drinking may have been exaggerated. [ 21 ] [ 22 ]  The  gut microbiome  of a typical healthy individual naturally ferments small amounts of ethanol, and in rare cases dysbiosis leads to  auto-brewery syndrome , therefore whether benefits of alcohol are derived from the behavior of consuming alcoholic drinks or as a homeostasis factor in normal physiology via metabolites from commensal microbiota remains unclear. [ 23 ] [ 24 ]


In 2012, researchers at UCLA found that tiny amounts (1 mM, or 0.005%) of ethanol doubled the lifespan of  Caenorhabditis elegans , a roundworm frequently used in biological studies, that were starved of other nutrients. Higher doses of 0.4% provided no longevity benefit. [ 25 ]  However, worms exposed to 0.005% did not develop normally (their development was arrested). The authors argue that the worms were using ethanol as an alternative energy source in the absence of other nutrition, or had initiated a stress response. They did not test the effect of ethanol on worms fed a normal diet.


In 2010, a paper in the journal  Environmental Toxicology & Chemistry  showed that low doses of  methylmercury , a potent neurotoxic pollutant, improved the hatching rate of  mallard  eggs. [ 26 ]  The author of the study, Gary Heinz, who led the study for the  U.S. Geological Survey  at the  Patuxent Wildlife Research Center  in  Beltsville , stated that other explanations are possible. For instance, the flock he studied might have harbored some low, subclinical infection and that mercury, well known to be antimicrobial, might have killed the infection that otherwise hurt reproduction in the untreated birds. [ 26 ]


Hormesis has been observed in a number of cases in humans and animals exposed to chronic low doses of ionizing radiation. A-bomb survivors who received high doses exhibited shortened lifespan and increased cancer mortality, but those who received low doses had lower cancer mortality than the Japanese average. [ 27 ] [ 28 ]


In Taiwan, recycled  radiocontaminated  steel was inadvertently used in the construction of over 100 apartment buildings, causing the long-term exposure of 10,000 people. The average dose rate was 50 mSv/year and a subset of the population (1,000 people) received a total dose over 4,000 mSv over ten years. In the widely used  linear no-threshold model  used by regulatory bodies, the expected cancer deaths in this population would have been 302 with 70 caused by the extra ionizing radiation, with the remainder caused by natural background radiation. The observed cancer rate, though, was quite low at 7 cancer deaths when 232 would be predicted by the LNT model had they not been exposed to the radiation from the building materials. Ionizing radiation hormesis appears to be at work. [ 29 ]


No experiment can be performed in perfect isolation. Thick lead shielding around a chemical dose experiment to rule out the effects of ionizing radiation is built and rigorously controlled for in the laboratory, and certainly not the field. Likewise the same applies for ionizing radiation studies. Ionizing radiation is released when an unstable particle releases radiation, creating two new substances and energy in the form of an  electromagnetic wave . The resulting materials are then free to interact with any environmental elements, and the energy released can also be used as a catalyst in further ionizing radiation interactions. [ 30 ]


The resulting confusion in the low-dose exposure field (radiation and chemical) arise from lack of consideration of this concept as described by Mothersill and Seymory. [ 31 ]


Veterans of the  Gulf War  (1991) who suffered from the persistent symptoms of  Gulf War Illness  (GWI) were likely exposed to stresses from toxic chemicals and/or radiation. [ 32 ]   The DNA damaging ( genotoxic ) effects of such exposures can be, at least partially, overcome by the DNA  nucleotide excision repair  (NER) pathway.   Lymphocytes  from GWI veterans exhibited a significantly elevated level of NER repair. [ 32 ]   It was suggested that this increased NER capability in exposed veterans was likely a hormetic response, that is, an induced protective response resulting from battlefield exposure. [ 32 ]


One of the areas where the concept of hormesis has been explored extensively with respect to its applicability is aging. [ 33 ] [ 34 ]  Since the basic survival capacity of any biological system depends on its  homeostatic  ability,  biogerontologists  proposed that exposing cells and organisms to mild stress should result in the adaptive or hormetic response with various biological benefits. This idea has preliminary evidence showing that repetitive mild stress exposure may have anti-aging effects in laboratory models. [ 35 ] [ 36 ]  Some mild stresses used for such studies on the application of hormesis in aging research and interventions are  heat shock , irradiation,  prooxidants ,  hypergravity , and food restriction. [ 35 ] [ 36 ] [ 37 ]  Such compounds that may modulate stress responses in cells have been termed "hormetins". [ 35 ]


Hormesis suggests dangerous substances have benefits. Concerns exist that the concept has been leveraged by  lobbyists  to weaken environmental regulations of some well-known toxic substances in the US. [ 38 ]


The hypothesis of hormesis has generated the most controversy when applied to  ionizing radiation . This hypothesis is called radiation hormesis. For policy-making purposes, the commonly accepted model of dose response in radiobiology is the  linear no-threshold model  (LNT), which assumes a strictly linear dependence between the risk of radiation-induced adverse health effects and radiation dose, implying that there is no safe dose of radiation for humans.


Nonetheless, many countries including the  Czech Republic ,  Germany ,  Austria ,  Poland , and the  United States  have  radon therapy  centers whose whole primary operating principle is the assumption of radiation hormesis, or beneficial impact of small doses of radiation on human health. Countries such as Germany and Austria at the same time have imposed very strict antinuclear regulations, which have been described as  radiophobic  inconsistency.


The  United States National Research Council  (part of the  National Academy of Sciences ), [ 39 ]  the  National Council on Radiation Protection and Measurements  (a body commissioned by the  United States Congress ) [ 40 ]  and the United Nations Scientific Committee on the Effects of Ionizing Radiation  all agree that radiation hormesis is not clearly shown, nor clearly the rule for radiation doses.


A United States–based  National Council on Radiation Protection and Measurements  stated in 2001 that  evidence for radiation hormesis is insufficient and radiation protection authorities should continue to apply the LNT model for purposes of risk estimation. [ 40 ]


A 2005 report commissioned by the French National Academy concluded that evidence for hormesis occurring at low doses is sufficient  and LNT should be reconsidered as the methodology used to estimate risks from low-level sources of radiation, such as  deep geological repositories  for  nuclear waste . [ 41 ]


Hormesis remains largely unknown to the public, requiring a policy change for a possible toxin to consider exposure risk of small doses. [ 42 ]


Idiosyncratic drug reactions , also known as  type B reactions , are  drug reactions  that occur rarely and unpredictably amongst the population. This is not to be mistaken with  idiopathic , which implies that the cause is not known. They frequently occur with exposure to new drugs, as they have not been fully tested and the full range of possible side-effects have not been discovered; they may also be listed as an  adverse drug reaction  with a drug, but are extremely rare. Some patients have  multiple- drug intolerance . Patients who have multiple idiopathic effects that are nonspecific are more likely to have anxiety and depression. [ 1 ]  Idiosyncratic drug reactions appear to not be concentration dependent. A minimal amount of drug will cause an immune response, but it is suspected that at a low enough concentration, a drug will be less likely to initiate an  immune response .


In adverse drug reactions involving overdoses, the toxic effect is simply an extension of the pharmacological effect (Type A adverse drug reactions). On the other hand, clinical symptoms of idiosyncratic drug reactions (Type B adverse drug reactions) are different from the pharmacological effect of the drug.


The proposed mechanism of most idiosyncratic drug reactions is immune-mediated toxicity. To create an immune response, a foreign molecule must be present that antibodies can bind to (i.e. the antigen) and cellular damage must exist. Very often, drugs will not be immunogenic because they are too small to induce immune response. However, a drug can cause an immune response if the drug binds a larger molecule. Some unaltered drugs, such as  penicillin , will bind avidly to proteins. Others must be bioactivated into a toxic compound that will in turn bind to proteins. The second criterion of cellular damage can come either from a toxic drug/drug metabolite, or from an injury or infection.
These will sensitize the immune system to the drug and cause a response.
Idiosyncratic reactions fall conventionally under toxicology.


Kindling  due to  substance withdrawal  is the neurological condition which results from repeated withdrawal episodes from  sedative–hypnotic drugs  such as  alcohol  and  benzodiazepines .


Each withdrawal leads to more severe withdrawal symptoms than in previous episodes. Individuals who have had more withdrawal episodes are at an increased risk of very severe withdrawal symptoms, up to and including seizures and death. Long-term activation of the  GABA receptor  by sedative–hypnotic drugs causes chronic GABA  receptor downregulation  as well as  glutamate  overactivity, which can lead to drug and neurotransmitter  sensitization ,  central nervous system  hyperexcitability, and  excitotoxicity .


Binge drinking  is believed to increase impulsivity due to altered functioning of prefrontal–subcortical and orbitofrontal circuits. Binge drinking in alcoholics who have undergone repeated detoxification is associated with an inability to interpret  facial expressions  properly; this is believed to be due to kindling of the amygdala with resultant distortion of neurotransmission. Adolescents, females and young adults are most sensitive to the neuropsychological effects of binge drinking. Adolescence, particularly early adolescence, is a developmental stage which is particularly vulnerable to the neurotoxic and neurocognitive adverse effects of binge drinking due to it being a time of significant brain development. [ 1 ]


Approximately 3 percent of people who are alcohol dependent experience psychosis during acute intoxication or withdrawal. Alcohol-related psychosis may manifest itself through a kindling mechanism. The mechanism of alcohol-related  psychosis  is due to distortions to neuronal membranes,  gene expression , as well as  thiamine  deficiency. It is possible in some cases that alcohol abuse via a kindling mechanism can cause the development of a chronic substance-induced psychotic disorder (e.g., schizophrenia). The effects of an alcohol-related psychosis include an increased risk of depression and suicide as well as psychosocial impairments. [ 2 ]


Repeated acute intoxication followed by acute withdrawal is associated with profound behavioural changes and neurobiological alterations in several brain regions. Much of the documented evidence of kindling caused by repeated detoxification regards increased seizure frequency. Increased fear and anxiety and cognitive impairments are also  associated with alcohol withdrawal kindling due to binge drinking or alcoholics with repeated  alcohol withdrawal  experiences. The impairments induced by binge drinking or repeated detoxification of alcoholics cause a loss of behavioural inhibition of the prefrontal cortex; the  prefrontal cortex  is mediated by subcortical systems such as the amygdala. This loss of behavioral control due to brain impairment predisposes an individual to  alcoholism  and increases the risk of an abstaining alcoholic relapsing. This impairment may also result in long-term adverse effects on emotional behavior. Impaired associative learning may make behavioural therapies involving conditioning approaches for alcoholics less effective. [ 1 ]


Binge drinking regimes are associated with causing an imbalance between  inhibitory  and  excitatory   amino acids  and changes in  monoamine  release in the central nervous system, which increases neurotoxicity; this may result in cognitive impairments, psychological problems, and may cause irreversible brain damage in both adolescent and adult long-term binge drinkers. [ 3 ] [ 4 ]  Similar to binge drinkers, individuals suffering from  alcohol dependence  develop changes to neurotransmitter systems, which occur as a result of kindling and sensitization during withdrawal. This progressively lowers the threshold needed to cause  alcohol-related brain damage  and cognitive impairments, leading to altered neurological function. The changes in activity of excitatory and inhibitory neurotransmitter systems is similar to that which occurs in individuals suffering from limbic or  temporal lobe epilepsy . [ 5 ]


Adaptational changes at the GABA A  benzodiazepine receptor complex do not fully explain  tolerance ,  dependence , and  withdrawal  from benzodiazepines. Other receptor complexes may be involved; in particular, the excitatory  glutamate  system is implicated. The involvement of glutamate in  benzodiazepine dependence  explains long-term potentiation as well as neuro-kindling phenomena. There is some evidence that a prior history of CNS depressant dependence (e.g. alcohol) increases the risk of dependence on benzodiazepines. Tolerance to drugs is commonly believed to be due to receptor  down-regulation ; however, there is very limited evidence to support this, and this hypothesis comes from animal studies using very high doses. Instead, other mechanisms, such as  receptor uncoupling , may play a more important role in the development of benzodiazepine dependence; this may lead to prolonged conformational changes in the receptors or altered subunit composition of the receptors. [ 6 ]


Repeated benzodiazepine withdrawal episodes may result in similar neuronal kindling as that seen after repeated withdrawal episodes from alcohol, with resultant increased neuro-excitability. The glutamate system is believed to play an important role in this kindling phenomenon with AMPA receptors which are a subtype of glutamate receptors being altered by repeated withdrawals from benzodiazepines. The changes which occur after withdrawal in AMPA receptors in animals have been found in regions of the brain which govern anxiety and seizure threshold; thus kindling may result in increased severity of anxiety and a lowered seizure threshold during repeated withdrawal. Changes in the glutamate system and GABA system may play an important role at different time points during  benzodiazepine withdrawal syndrome . [ 6 ]


Binge drinking may induce brain damage due to the repeated cycle of acute intoxication followed by an acute abstinence withdrawal state. [ 7 ]  Based on animal studies, regular binge drinking in the long-term is thought to be more likely to result in brain damage than chronic (daily) alcoholism. This is due to the 4- to 5-fold increase in glutamate release in nucleus accumbens during the acute withdrawal state between binges but only in dose 3 g/kg, in 2 g/kg there is no increase in glutamate release. In contrast, during withdrawal from chronic alcoholism only a 2- to 3-fold increase in glutamate release occurs. The high levels of glutamate release causes a chain reaction in other neurotransmitter systems. The reason that chronic sustained alcoholism is thought by some researchers to be less brain damaging than binge drinking is because tolerance develops to the effects of alcohol and unlike binge drinking repeated periods of acute withdrawal does not occur, [ 3 ] [ 4 ]  but there are also many alcoholics who typically drink in binges followed by periods of no drinking. [ 8 ]   Excessive glutamate release is a known major cause of neuronal cell death. Glutamate causes  neurotoxicity  due to  excitotoxicity  and oxidative glutamate toxicity. Evidence from animal studies suggests that some people may be more genetically sensitive to the neurotoxic and brain damage associated with binge drinking regimes. Binge drinking activates microglial cells which leads to the release of inflammatory  cytokines  and mediators such as  tumour necrosis factor , and  nitric oxide  causing  neuroinflammation  leading to neuronal destruction. [ 3 ] [ 4 ]


Repeated acute withdrawal from alcohol which occurs in heavy binge drinkers has been shown in several studies to be associated with cognitive deficits as a result of neural kindling; neural kindling due to repeated withdrawals is believed to be the mechanism of cognitive damage in both binge drinkers and alcoholics. Neural kindling may explain the advancing pathogenesis and progressively deteriorating course of alcoholism and explain continued alcohol abuse as due to avoidance of distressing acute withdrawal symptoms which get worse with each withdrawal. Multiple withdrawals from alcohol is associated with long-term nonverbal memory impairment in adolescents and to poor memory in adult alcoholics. Adult alcoholics who experienced two or more withdrawals showed more frontal lobe impairments than alcoholics who had a history of one or no prior alcohol withdrawals. The finding of kindling in alcoholism is consistent with the mechanism of brain damage due to binge drinking and subsequent withdrawal. [ 9 ]


Kindling refers to the phenomenon of increasingly severe withdrawal symptoms, including an increased risk of seizures, that occurs as a result of repeated withdrawal from alcohol or other sedative–hypnotics with related modes of action.  Ethanol  (alcohol) has a very similar mechanism of tolerance and withdrawal to benzodiazepines, involving the  GABA A
 receptors ,  NMDA receptors  and  AMPA receptors , but the majority of research into kindling has primarily focused on alcohol. [ 6 ]  An intensification of anxiety and other psychological symptoms of alcohol withdrawal also occurs. [ 10 ]


Failure to manage the alcohol withdrawal syndrome appropriately can lead to permanent brain damage or death. [ 11 ]


Acamprosate , a drug used to promote abstinence from alcohol, an  NMDA antagonist  drug, reduces excessive glutamate activity in the central nervous system and thereby may reduce excitotoxicity and withdrawal related brain damage. [ 12 ] [ 13 ]


Monitored Emergency Use of Unregistered and Investigational Interventions  ( MEURI ) is an  ethical protocol  developed by the  World Health Organization  to evaluate the potential use of experimental drugs in the event of  public health emergencies . [ 1 ] [ 2 ]
The protocol was created by the  WHO Ebola Ethics Working Group  in 2014 [ 3 ] [ 4 ]  in the context of the  2014 West Africa Ebola outbreak . The WHO recommends that the term be preferred to the term " compassionate use " or " expanded access " for the controlled use of unregistered treatments in public health emergency measures. [ 5 ] [ 6 ]


Morning pseudoneutropenia  is a transient reduction in the measured neutrophil count from peripheral samples. This is noticed in some patients who are taking  antipsychotic  medication. Morning pseudoneutropenia is thought to be due to  diurnal variation  in the amount of circulating white blood cells and changes in the levels of hematopoietic  cytokines  and  granulocyte colony stimulating factor  (GCSF). [ 1 ]   Antipsychotics may amplify the natural variation in these hematopoietic factors. [ citation needed ]


Neutropenia  is a hematological disorder characterized by an abnormally low number of  neutrophils  in the blood.  Neutrophils usually make up 50-70% of circulating white blood cells and serve as the primary defense against infections.  There is some variability in the neutrophil counts depending upon when the sample is taken, where the blood sample is taken from, and the system used by the  medical lab  for measuring the blood cells, but any significant reduction in function or number below the appropriate  range may predispose individuals to infections. [ citation needed ]


Case reports of such incidents are reported with  clozapine , [ 2 ] [ 3 ]   risperidone , [ 4 ]  and  aripiprazole . [ 5 ]


These case reports suggest that the observed cases of the morning pseudoneutropenia did not proceed to become  agranulocytosis  which is a significant and dangerous side effect of some of antipsychotics. Hence it was suggested [ 6 ]  that although the morning neutrophil count may appear low, if the antipsychotic medication were considered efficacious then white cell counts may be repeated in the afternoon prior to making a decision based only on the morning counts. [ citation needed ]


The  National Institute for Health and Care Excellence  ( NICE ) is an executive  non-departmental public body  of the  Department of Health and Social Care . [ 1 ]


As the national  health technology assessment  body of England, it is responsible for judging the cost-effectiveness of medicines and making them available on the NHS through reimbursement, with its judgements informing decisions in Wales and Northern Ireland. [ 2 ] [ 3 ]  It also provides a range of clinical guidance to the NHS in England and Wales, which are considered by Northern Ireland. [ 2 ] [ 3 ] [ 4 ]


It was set up as the  National Institute for Clinical Excellence  in 1999, and on 1 April 2005 joined with the  Health Development Agency  to become the new  National Institute for Health and Clinical Excellence [ 5 ] [ 6 ]  (still abbreviated as NICE). Following the  Health and Social Care Act 2012 , NICE was renamed the National Institute for Health and Care Excellence on 1 April 2013 reflecting its new responsibilities for social care, and changed from a  special health authority  to an executive non-departmental public body (NDPB).


NICE was established in an attempt to end the so-called  postcode lottery  of healthcare in England and Wales, where availability of  treatments depended on the NHS Health Authority area in which the patient happened to live, but it has since acquired a high reputation internationally as a role model for the development of clinical guidelines. One aspect of this is the explicit determination of cost–benefit boundaries for certain technologies that it assesses. [ 7 ]  NICE also plays an important role in pioneering technology assessment in other healthcare systems through NICE International, established in May 2008 to help cultivate links with foreign governments. [ 8 ]  NICE International has received financial support from the  Bill & Melinda Gates Foundation  and  Rockefeller Foundation . [ 9 ]


The notion of an Institute to determine the clinical effectiveness of interventions first emerged at the end of  John Major 's Conservative Government as moves elsewhere were being made to set professionally agreed standards for clinical care. In 1997, the  UK National Screening Committee  (NSC) had been established by  Sir Kenneth Calman  and  Muir Gray  (now Sir Muir Gray) by the Policy Team led by Timothy Riley for the Department of Health. [ 10 ]  The NSC aimed to ensure that  evidence-based medicine  informed policy making on what national screening programmes were approved for funding and what quality assurance mechanisms should be in place. This was a timely action as screening quality in breast cancer screening services came under question at Exeter in 1997 [ 11 ]  and followed in the wake of the 1995  Calman-Hine Report . [ 12 ]


The idea of what was originally called the National Institute for Clinical Excellence took root when Labour came to power in 1997.  Frank Dobson  became Secretary of State and was supported by a team of Ministers keen on introducing clinical and health outcome measures to achieve improvements in the quality and delivery of care. The team included  Alan Milburn ,  Baroness Margaret Jay , and  Tessa Jowell . The name and mission was agreed in a meeting between the Ministerial team, Timothy Riley and Felicity Harvey shortly after the election and it was agreed that NICE should be described in the first policy  white paper , The New NHS: Modern, Dependable 1997. [ 13 ]  Timothy Riley led the team that developed the policy and for NICE and which managed the legislation through Parliament in addition to implementing the new institute as a  Special Health Authority . Timothy Riley joined  Sir Michael Rawlins  (the then recently appointed Chair of NICE) at the  Health Select Committee  in February 1999 where questions were raised as to whether NICE was just a means to "ration" healthcare. Sir Michael Rawlins and Timothy Riley presented a compelling case that positioned NICE as a standards setting body first and foremost. [ 14 ]
However, the reality was that although NICE was principally aimed at aligning professional standards through clinical guidelines and audit, the acceptability of drugs, devices and technological interventions in defining those standards, could not be ignored and so the concept of a "fourth hurdle" for drugs accessing the NHS market was invoked. This controversial policy shift meant that NICE was critical for decisions on drug reimbursement. Indeed, the first drug appraisal by NICE was on the drug  Relenza  which was turned down amidst criticisms from  Glaxo-Wellcome  that the appraisal had been fast tracked. [ 15 ]  Later, this policy development whereby the criteria for decision making, the role of costs, and the degree to which decisions of NICE and the secretary of state would be binding on clinicians was analysed by  Andrew Dillon , Trevor Gibbs, Timothy Riley, and  Trevor A. Sheldon . [ 16 ]  As of 1 February 2022, its chief executive is Samantha Roberts, who succeeded  Gillian Leng . [ 17 ]


NICE publishes guidelines in four areas:


These appraisals are based primarily on  evidence-based  evaluations of efficacy, safety and cost-effectiveness in various circumstances.


Since January 2005, the NHS in  England  has been legally obliged to provide funding for medicines and treatments recommended by NICE's technology appraisal board. [ 18 ]  This was at least in part as a result of well-publicised postcode lottery anomalies in which certain less-common treatments were funded in some parts of the UK but not in others due to local decision making in the NHS. [ 19 ] [ 20 ] [ 21 ]


Before an appraisal, the Advisory Committee on Topic Selection draws up a list of potential topics of clinical significance for appraisal. The  Secretary of State for Health and Social Care  must then refer any technology so that the appraisal process can be formally initiated. Once this has been done NICE works with the Department of Health to draw up the scope of the appraisal. [ citation needed ]


NICE then invites consultee and commentator organisations to take part in the appraisal. A consultee organisation would include patient groups, organisations representing health care professionals and the manufacturers of the product undergoing appraisal. Consultees submit evidence during the appraisal and comment on the appraisal documents. Commentator organisations include the manufacturers of products to which the product undergoing appraisal is being compared. They comment on the documents that have been submitted and drawn up but do not actually submit information themselves. [ citation needed ]


An independent academic centre then draws together and analyses all of the published information on the technology under appraisal and prepares an assessment report. This can be commented on by the Consultees and Commentators. Comments are then taken into account and changes made to the assessment report to produce an evaluation report. An independent Appraisal Committee then looks at the evaluation report, hears spoken testimony from clinical experts, patient groups and carers. They take their testimony into account and draw up a document known as the 'appraisal consultation document'. This is sent to all consultees and commentators who are then able to make further comments. Once these comments have been taken into account the final document is drawn up called the 'final appraisal determination'. This is submitted to NICE for approval. [ 22 ]


The process aims to be fully independent of government and lobbying power, basing decisions fully on clinical and cost-effectiveness. There have been concerns that  lobbying  by pharmaceutical companies to mobilise media attention and influence public opinion are attempts to influence the decision-making process. [ 23 ]  A fast-track assessment system has been introduced to reach decisions where there is most pressure for a conclusion. [ citation needed ] [ 24 ]


NICE carries out assessments of the most appropriate treatment regimes for different diseases. This must take into account both desired medical outcomes (i.e. the best possible result for the patient) and also economic arguments regarding differing treatments. [ 25 ]


NICE has set up several National Collaborating Centres bringing together expertise from the royal medical colleges, professional bodies and patient/carer organisations which draw up the guidelines. The centres are the National Collaborating Centre for Cancer, the National Clinical Guideline Centre, the National Collaborating Centre for Women and Children´s Health, and the  National Collaborating Centre for Mental Health . [ 26 ]


The National Collaborating Centre appoints a Guideline Development Group whose job it is to work on the development of the clinical guideline. This group consists of medical professionals, representatives of patient and carer groups and technical experts. They work together to assess the evidence for the guideline topic (e.g.  clinical trials  of competing products) before preparing a draft guideline. There are then two consultation periods in which stakeholder organisations are able to comment on the draft guideline. After the second consultation period, an independent Guideline Review Panel reviews the guideline and stakeholder comments and ensures that these comments have been taken into account. The Guideline Development Group then finalises the recommendations and the National Collaboration Centre produces the final guideline. This is submitted to NICE to formally approve the guideline and issue the guidance to the NHS. [ citation needed ]  To date NICE has produced more than 200 different guidelines. [ 27 ]


In October 2014  Andy Burnham  said that a Labour government could reduce variation in access to drugs and procedures by making it mandatory for commissioners to follow NICE clinical guidelines. "We need to look at how you strengthen NICE. Where they have said something is effective and affordable, on what basis does a local commissioner withhold that from somebody? I’m not comfortable with that. I don’t support that." [ 28 ]


NICE has a service called Clinical Knowledge Summaries (CKS) which provides primary care practitioners with a readily accessible summary of the current evidence base and practical guidance. [ 29 ] [ 30 ]


In 2022  PricewaterhouseCoopers  did a study for the  Association of the British Pharmaceutical Industry  of 13 medicines recommended for asthma, kidney disease, stroke prevention and type 2 diabetes.  They found that  1.2 million patients had not received the drugs which could have given them the equivalent of 429,000 extra years in “complete good health” which could have translated into £17.9bn in “productivity gains” for the British economy. [ 31 ]


Under the  Health and Social Care Act 2012 , NICE was given responsibility for developing guidance and quality standards for  social care , using an evidence-based model. This was delivered by the NICE Collaborating Centre for Social Care (NCCSC), hosted by the  Social Care Institute for Excellence  (SCIE) and four partner organisations - Research in Practice, Research in Practice for Adults, Personal Social Services Research Unit and the  EPPI-Centre . Over a five year period, the NCCSC developed social care guidelines and supported the implementation of both the guidelines and social care quality standards. [ 32 ]


NICE received referrals for social care guidance from the Department of Health and the  Department for Education , and commission the guidance from the NCCSC. NICE, along with the NCCSC, carried out a  scoping exercise  with a scoping group and with input from key stakeholders, at both a workshop and a public consultation, to ensure the guidance to be produced was focused and achievable. A  chairperson  and members of the Guidance Development Group were appointed, and posed review questions which enabled  systematic evidence reviews  to take place, thus delivering the guidance and subsequent recommendations. Service user and carer involvement took place throughout, as well as public consultation on the draft guidance.


The Guidance Development Group then finalised the recommendations and the NCCSC produced the final guideline. This was submitted to NICE for formal approval and publication. The entire process from pre-scoping to publication took approximately 24 months. The guidance was then available to NICE standing committees to develop a quality standard on the topic. The quality standard was developed using the guidance and other accredited sources, to produce high-level concise statements that can be used for quality improvement by social care providers and commissioners, as well as setting out what service users and carers can expect of high quality social care services.


The NCCSC is unique within NICE, in that it is the only collaborating centre to have responsibility for the adoption and dissemination support for guidance and quality standards in the  social care arena . Drawing on the expertise of SCIE and their partners within the sector, each of the guidance products and quality standards had a needs assessment carried out to determine the requirements for tools to help embed the guidance and quality standards within the sector. These could include tailored versions of guidance for specific audiences, costing and commissioning tools and even training and learning packages.


As of August 2013, NICE and the NCCSC had scheduled guidance delivery for five topics:  domiciliary care , older adults with long-term conditions, transition between health and social care settings, transition from children's to adults' services and  child abuse and neglect .


As with any system financing health care, the NHS has a limited budget and a vast number of potential spending options. Choices must be made as to how this limited budget is spent.  Economic evaluations  are carried out within a  health technology assessment  framework to compare the cost-effectiveness of alternative activities and to consider the  opportunity cost  associated with their decisions. [ 33 ]  By choosing to spend the finite NHS budget upon those treatment options that provide the most efficient results, society can ensure it does not lose out on possible health gains through spending on inefficient treatments and neglecting those that are more efficient.


NICE attempts to assess the cost–effectiveness of potential expenditures within the NHS to assess whether or not they represent 'better value' for money than treatments that would be neglected if the expenditure took place. It assesses the cost–effectiveness of new treatments by analysing the cost and benefit of the proposed treatment relative to the next best treatment that is currently in use. [ 34 ]


NICE guidance supports the use of  quality-adjusted life years  (QALY) as the primary outcome for quantifying the expected health benefits associated with a given treatment regime. By comparing the present value (see  discounting ) of expected QALY flows with and without treatment, or relative to another treatment, the net/relative health benefit derived from such a treatment can be derived. When combined with the relative cost of treatment, this information can be used to estimate an  incremental cost-effectiveness ratio  (ICER), which is considered in relation to NICE's threshold willingness-to-pay value. [ 33 ]


As a guideline rule, NICE accepts as cost-effective those interventions with an incremental cost-effectiveness ratio of less than £20,000 per QALY and that there should be increasingly strong reasons for accepting as cost-effective interventions with an incremental cost-effectiveness ratio of over a threshold of £30,000 per QALY. [ 35 ]


Over the years, there has been great controversy as to what value this threshold should be set at. Initially, there was no fixed number. But the appraisal teams created a consensus amount of about £30,000. However, in November 2008  Alan Johnson , the then Secretary of State, announced that for end-of-life cancer drugs the threshold could be increased above £30,000. [ 36 ]


The first drug to go through the new process was  lenalidomide , whose ICER was £43,800. [ 37 ]


The following example from NICE explains the QALY principle and the application of the cost per QALY calculation.


A patient has a life-threatening condition and is expected to live on average for one year receiving the current best treatment which costs the NHS £3,000. A new drug becomes available that will extend the life of the patient by three months and improve his or her quality of life, but the new treatment will cost the NHS more than three times as much at £10,000. Patients score their perceived quality of life on a scale from 0 to 1 with 0 being worst possible health and 1 being best possible health. On the standard treatment, quality of life is rated with a score of 0.4 but it improves to 0.6 with the new treatment. Patients on the new treatment on average live an extra 3 months, so 1.25 years in total. The quality of life gained is the product of  life span  and  quality rating  with the new treatment less the same calculation for the old treatment, i.e. (1.25 x 0.6) less (1.0 x 0.4) = 0.35 QALY. The marginal cost of the new treatment to deliver this extra gain is £7,000 so the cost per quality life year gained is £7000/0.35 or £20,000. This is within the £20,000-£30,000 that is suggested by NICE to be the limit for drugs to be cost-effective. [ 38 ]


If the patient was expected to live only one month extra and instead of three then NICE would issue a recommendation not to fund. The patient's  primary care trust [ needs update ]  could still decide to fund the new treatment, but if not, the patient would then have two choices. He or she could opt to take the free NHS standard treatment, or he or she may decide to pay out of pocket to obtain the benefit of the new treatment from a different health care provider. If the person has a private health insurance policy the person could check to see whether the private insurance provider will fund the new treatment. About 8% of the population has some private health insurance from an employer or trade association and 2% pay from their own resources.


Theoretically, it might be possible to draw up a table of all possible treatments sorted by cost per QALY gained. Those treatments with lowest cost per QALY gained would appear at the top of the table and deliver the most benefit per value spent and would be easiest to justify funding for. Those where the delivered benefit is low and the cost is high would appear at the bottom of the list. Decision makers would, theoretically, work down the table, adopting services that are the most cost effective. The point at which the NHS budget is exhausted would reveal the  shadow price , the threshold lying between the CQG (cost per QALY gained) of the last service that is funded and that of the next most cost effective service that is not funded.


In practice this exercise is not done, but an assumed shadow price has been used by NICE for many years in its assessments to determine which treatments the NHS should and should not fund. NICE states that for drugs the CQG should not normally exceed £30,000 but that there is not a hard threshold, [ 39 ]  though research has shown that any threshold is "somewhat higher" than being in the range £35,000 - £40,000. [ 40 ]


The  House of Commons Health Select Committee , in its report on NICE, stated in 2008 that "the ... cost-per-QALY it uses to decide whether a treatment is cost-effective is of serious concern. The threshold it employs is not based on empirical research and is not directly related to the NHS budget, nor is it at the same level as that used by  primary care trusts  (PCTs) in providing treatments not assessed by NICE, which tends to be lower. Some witnesses, including patient organisations and pharmaceutical companies, thought NICE should be more generous in the cost per QALY threshold it uses, and should approve more products. On the other hand, some PCTs struggle to implement NICE guidance at the current threshold and other witnesses argued that a lower level should be used. However, there are many uncertainties about the thresholds used by PCTs." It went on to recommend that "an independent body should determine the threshold used when making judgements of the value of drugs to the NHS." [ 41 ]


The work that NICE is involved in, attracts the attention of many groups, including doctors, the pharmaceutical industry, and patients. NICE is often associated with controversy, because the requirement to make decisions at a national level, can conflict with what is (or is believed to be) in the best interests of an individual patient.


Approved cancer drugs and treatments such as  radiotherapy  and  chemotherapy  are funded by the NHS without any financial contribution being taken from the patient. Where NICE has approved a treatment, the NHS must fund it. But not all treatments have been assessed by NICE and these treatments are usually dependent on local NHS decision making. In the case of cancer the  Cancer Drugs Fund  was set up in 2011 after complaints about NICE decisions on new and expensive cancer drugs with limited benefits. [ citation needed ]  Treatment for fertility problems are approved but not always funded by  clinical commissioning groups  and they may cap the number of rounds. [ 42 ]


NICE has been criticised for being too slow to reach decisions. On one occasion, the  Royal National Institute of Blind People  said it was outraged over its delayed decision for further guidance regarding two drugs for  macular degeneration  that are already approved for use in the NHS. However the Department of Health said that it had 'made it clear to PCTs that funding for treatments should not be withheld simply because guidance from NICE is unavailable'. [ 43 ]


Some of the more controversial NICE decisions have concerned  donepezil ,  galantamine ,  rivastigmine  (review) and  memantine  for the treatment of  Alzheimer's disease  and  bevacizumab ,  sorafenib ,  sunitinib  and  temsirolimus  for  renal cell carcinoma . All these are drugs with a high cost per treatment and NICE has either rejected or restricted their use in the NHS on the grounds that they are not cost-effective.


A statement published by the Royal College of Physicians expressed concern that the 2021 NICE guidelines for ME/CFS did not properly evaluate or recommend graded exercise therapy and cognitive behavioral therapy for the treatment of ME/CFS. [ 44 ]  A study by 49 academics argued that the dissonance between the 2021 guidelines and the previous guideline was the result of deviating from usual scientific standards of the NICE process. [ 45 ]  NICE responded that they did follow the standard  GRADE approach , and evidence from  unblinded trials  with subjective outcomes was appropriately downgraded. [ 46 ]


A Conservative shadow minister once criticized NICE for spending more on communications than assessments. In its defence, NICE said the majority of its communications budget was spent informing doctors about which drugs had been approved and new guidelines for treatments and that the actual cost of assessing new drugs for the NHS includes money spent on NICE's behalf by the Department of Health. When these were added to NICE's own costs, the total cost of the technology appraisal programme far outstrips the cost of NICE communications.


A report from the  University of York  Centre for Health Economics written by  Karl Claxton  in February 2015 suggested that the maximum threshold, currently around £30,000 a year, for judging a medicine cost-effective should be more than halved. They found that any intervention costing more than £13,000 per  quality-adjusted life year  risked causing more harm than good by denying cost effective treatment to other patients. [ 47 ]


The institute's approach to the introduction of new oral therapy for  hepatitis C  has been criticised.  Sofosbuvir  was approved in 2015. It costs about £30,000 for 12 weeks treatment.  NHS England  established 22 Operational Delivery Networks to roll out delivery and proposes to fund 10,000 courses of treatment in 2016-17. Each has been given a “run rate” of how many patients they are allowed to treat. This is the NHS’ single biggest new treatment investment this year. [ 48 ]  In the North East London network patients with  cirrhosis  or  fibrosis  go to the front of the queue and three new patients at the Grahame Hayton Unit at the  Royal London Hospital  start treatment each month. Those without such complications may faced considerable delays before they start treatment. [ 49 ]


Opioid rotation  or  opioid switching  is the process of changing one opioid to another to improve  pain  control or reduce unwanted  side effects . [ 1 ]  This technique was introduced in the 1990s to help manage severe chronic pain and improve the opioid response in  cancer  patients. [ 2 ]  In order to obtain adequate levels of pain relief, patients requiring chronic opioid therapy may require an increase in the original prescribed dose for a number of reasons, including increased pain or a worsening disease state. [ 3 ]  Over the course of long-term treatment, an increase in dosage cannot be continued indefinitely as unwanted side effects of treatment often become intolerable once a certain dose is reached, even though the pain may still not be properly managed. One strategy used to address this is to switch the patient between different opioid drugs over time, usually every few months. [ 4 ]  Opioid rotation requires strict monitoring in patients with ongoing levels of high opioid doses for extended periods of time, since long term opioid use can lead to a patient developing  tolerance  to the analgesic effects of the drug. [ 5 ]  Patients may also not respond to the first opioid prescribed to them at all, therefore needing to try another opioid to help manage their pain. [ 3 ]  A patient's specific response and sensitivity to opioids include many factors that include physiology, genetics and pharmacodynamic parameters, which together determine the amount of pain control and tolerance of a particular opioid. [ 4 ]


Opioid analgesic drugs tend to exhibit incomplete  cross-tolerance , so that even when a patient has developed a high level of tolerance to one drug from this class, they may find that a different opioid drug will still be effective. [ 6 ]  The reasons for this are still not completely understood, but are thought to result from variations in  opioid receptor   affinity  and occupancy levels at  equianalgesic  doses, as well as additional mechanisms of action possessed by some drugs such as the  NMDA antagonist  action of  methadone  or  levorphanol , or the  SNRI  activity of  tramadol  or  tapentadol . [ 7 ] [ 8 ]


There are no clinical guidelines outlining the use and implementation of opioid rotation.  However, this strategy is commonly used for these various situations: pain not controlled by current opioid, pain controlled but in the presence of intolerable adverse events, pain not controlled despite rapid increase in opioid dose, switching to utilize different alternative routes of administration, or switching due to high cost of current opioid (or other patient-specific cost considerations). [ 1 ] [ 5 ] [ 9 ]


While there is good evidence for the efficacy of opioid rotation as a treatment approach in general [ citation needed ] , there is less evidence for what particular opioid analgesics are most suitable, and in practice the choice of opioid drugs used depends on many factors such as patient characteristics, prescriber preferences and safety. One issue with opioid rotation is that an opioid therapy failure poorly predicts whether other opioids would be effective. In certain situations, multiple switches may be required before pain therapy is optimized. [ 10 ]  In addition, recent studies explore which opioid drugs are most effective in implementing in an opioid rotation, but have so far found no difference in efficacy between opioid drugs like methadone and fentanyl in cancer patients. [ 11 ]


Diversion of prescribed opioid drugs for illicit recreational use is also a particular concern in this field, as the drugs which are most effective for relieving  suffering  in  palliative care  also tend to be those most sought after by  drug abusers . The choice of what opioid drug to use in which patient thus tends to be a balance between many different factors that must be considered, and the need for opioid rotation in chronic pain patients makes it advantageous for a wide range of different opioid drugs to be available, even though they may be broadly equivalent in action when used in shorter term treatment. [ 12 ] [ 13 ] [ 14 ] [ 15 ] [ 16 ] [ 17 ]  Additionally, newer studies may explore which patient populations can benefit the most from opioid rotation and which populations can have their pain managed by other means. [ citation needed ]


Ototoxicity  is defined as the toxic effect on the functioning of the inner ear, which may lead to temporary or permanent  hearing loss  (cochleotoxic) and balancing problems (vestibulotoxic). [ 1 ]  Drugs or pharmaceutical agents inducing ototoxicity are regarded as  ototoxic medications .


There is a wide range of ototoxic medications, for example,  antibiotics ,  antimalarials ,  chemotherapeutic agents ,  non-steroidal anti-inflammatory drugs (NSAIDs)  and  loop diuretics . [ 2 ]  While these drugs target on different body systems, they also trigger ototoxicity through different mechanisms, for example, destruction to cellular tissues of inner ear parts and disturbance on auditory nervous system. [ 2 ]


Onset of ototoxicity ranges from taking a single dose to long-term usage of the drugs. [ 3 ]  Signs and symptoms of ototoxicity include  tinnitus ,  hearing loss , dizziness and  nausea  and/or vomiting. [ 3 ]  The diagnosis of medicine-induced ototoxicity is challenging as it usually shows only mild symptoms in early stages. Thus, prospective ototoxicity monitoring would be required when patients are using ototoxic medications. [ 1 ]  Fortunately, the majority of ototoxicity cases are reversible by stopping the medication concerned.


Alcohol  is one of the leading substances known to have  ototoxic  effects. [ 4 ]  A 2023 systematic review and meta-analysis found that alcohol consumption is associated with an increased risk of  hearing loss . [ 5 ]


The most common classes of ototoxic medications include  antibiotics  (including  aminoglycosides  and  glycopeptides ) and  chemotherapeutic agents .  Aminoglycosides  and some chemotherapeutic agents are associated with both cochleotoxicity and vestibulotoxicity. They are thought to damage the hair cells of the  cochlea . Long-term exposure to these drugs may cause damage that progresses to the upper turn of the cochlea, impairing hearing or even causing deafness. [ 6 ]   Glycopeptides , on the other hand, are rarely associated with ototoxicity.


Aminoglycosides  are a class of antibiotics. The most frequently used aminoglycosides include  gentamicin ,  amikacin  and  streptomycin . These antibiotics are usually used in combination with other antimicrobial agents to treat drug-resistant organisms. For example, they are used with  β-lactam  for bacterial infections in  pneumonia . [ 7 ]  They are usually given either  intravenously  or  intramuscularly  due to their poor oral absorption.


Aminoglycosides irreversibly inhibit  protein synthesis  of bacteria, which specifically helps kill the  gram-negative bacteria . The drug is first transported into the bacterial cell and it binds to the  30S ribosomal subunit . [ 8 ]  This action interferes with the reading of codons during  mRNA translation , causing misreading and premature termination of the process. This inhibits  protein synthesis  and ultimately leads to the death of bacterial cells. [ 9 ]


All  aminoglycosides  can cause either reversible or irreversible ototoxicity. Ototoxicity is more frequently observed in individuals who received the treatment for more than five days and those who have  renal insufficiency . [ 7 ]  The mechanism of aminoglycosides-induced ototoxicity is not well understood. It is thought that because cochlear cells are rich in mitochondria, these antibiotics may also target cochlear cells and cause their death. [ 10 ]  Another hypothesis suggests that these drugs lead to the production of  reactive oxygen species  which generate oxidative stress and damage the inner ear. [ 11 ]


Glycopeptides  are another class of antibiotics.  Vancomycin  is the class originator for the glycopeptides. Lipoglycopeptides are a subclass of glycopeptides and they are derived from the structure of  vancomycin . Examples are  telavancin  and  dalbavancin . [ 7 ]


Vancomycin  and the lipoglycopeptides have slight differences in their mechanism of actions. Vancomycin inhibits  cell wall  synthesis of bacteria by preventing the cell wall component of bacteria,  peptidoglycan , from elongating and cross-linking. With weakened  peptidoglycan , the bacterial cell becomes susceptible to lysis. [ 9 ]  Lipoglycopeptides, additionally, can increase the membrane permeability of the bacterial cell and disrupt the bacterial cell membrane potential. [ 9 ]


This class of antibiotics can be used to treat skin or joint infections, where  gram-positive bacteria  are the pathogens responsible. Vancomycin is also used as an initial empirical treatment agent of community-acquired  bacterial meningitis  in locations where penicillin-resistant  S. pneumoniae  is common. [ 12 ]  This drug has other clinical uses, including  endocarditis  and  respiratory tract infections  caused by  Methicillin-resistant Staphylococcus aureus (MRSA) .


Case reports suggested that long-term use of vancomycin has been associated with ototoxicity. [ 13 ]  However, there is no well-established causal link between vancomycin and ototoxicity. For instance, preclinical studies showed that vancomycin had a low risk of inducing ototoxicity. [ 2 ]  Despite these findings, literature generally agreed that pre-existing hearing abnormalities, concomitant use of aminoglycosides and renal dysfunction are risk factors for vancomycin-induced ototoxicity. [ 14 ] [ 15 ]


Chemotherapeutic agents are drugs that are used in  chemotherapy  for the treatment of  cancer . Many of these agents are known to have the potential to cause hearing loss. Such agents include  cisplatin  and  bleomycin .


Cisplatin  is known as a platinum coordination complex.  Carboplatin  and  oxaliplatin  also belong to platinum coordination complexes, but they are less commonly associated with ototoxicity. These agents are used in the treatment of ovarian, head and neck, bladder, lung and colon cancers. Cisplatin and other platinum coordination complexes work by reacting with various sites on DNA in mainly cancer cells in order to form cross-links. The formed DNA-platinum complexes inhibit  replication  and  transcription , leading to miscoding and cell death. [ 7 ]


The mechanism of cisplatin in inducing ototoxicity is believed to involve the accumulation of  reactive oxygen species , which exert cytotoxic effect on cochlear cells. [ 16 ]  Some  pharmacogenetics  research have opened up new perspectives on the contributing factors of cisplatin-induced ototoxicity. They investigated several cancer-inducing  genes  and  genetic polymorphisms . Results showed that some  genes  are associated with protective effect on ototoxicity, while others may show no effect or even increased effect on ototoxicity. [ 10 ]


Bleomycin  is one of the antitumour antibiotics and is a fermentation product of  Streptomyces verticillus . It has a unique mechanism of action, making it an important agent in treating  Hodgkin disease  and testicular cancer. This unique chemotherapeutic agent causes oxidative damage to the  nucleotides  and leads to single- and double-stranded breaks in DNA. Excess breaks in DNA eventually causes cell death. [ 9 ]  Few case reports have identified the development of ototoxicity in some elderly patients who were administered with bleomycin. [ 17 ]  Since such cases are rare, the mechanisms behind have yet to be discovered.


Non-steroidal anti-inflammatory drugs (NSAIDs)  are one of the most recurrently used classes of drug clinically, indicated for anti-inflammatory, analgesic and  antipyretic  effects. [ 18 ]  Examples include high-dose  aspirin ,  ibuprofen  and  naproxen . Its therapeutic effect is achieved by inhibiting the activity of  cyclooxygenase  (COX), an enzyme mediating the biosynthesis of  prostaglandins  (PGs) and  thromboxanes  (TXAs). As this enzyme is inhibited,  prostaglandin  and  thromboxane  production is reduced, hence inhibiting the inflammatory response of pain and swelling caused by prostaglandin. [ 19 ]


Studies have proven that high-dose usage of aspirin can be associated with ototoxicity, manifesting reversible  hearing loss  and  tinnitus . [ 20 ]  The underlying mechanism is associated with a change in isolated cochlear outer  hair cells  (OHCs). Due to the COX inhibition, there is an increasing amount of  leukotrienes  in the inner ear. This leukotriene elevation leads to an alteration in the shape of isolated OHCs, thus disrupting their functions. Cochlear blood flow is eventually reduced, causing hearing impairment. [ 21 ]


Phosphodiesterase-5 (PDE-5) inhibitors  are the first-line drugs indicated for  erectile dysfunction  (ED), implying the sustained impairment of erectile functioning, which may lead to unsatisfactory sexual performance. [ 22 ]  Specific PDE-5 inhibitors are also approved for the treatment of  benign prostatic hyperplasia ,  pulmonary hypertension  and lower urinary tract symptoms. [ 23 ]  Common drug examples include  sildenafil ,  vardenafil  and  tadalafil . The enzyme PDE-5, found in the  corpus cavernosum  smooth muscle, is responsible for degrading  cyclic guanosine monophosphate  (cGMP) to 5-GMP. Inhibitors of this enzyme compete with cGMP for binding sites, which in turn increases the level of cGMP in smooth muscles. Through this mechanism, penis erection in male is eventually prolonged, resulting in a correction of ED. These drugs are known to cause headache, flushing and abnormal vision as their adverse effects.


PDE-5 inhibitors are also known for inducing sudden sensorineural hearing loss. It is mainly related to the obstruction and dysfunction of  eustachian tubes  which affects middle-ear pressure. Due to the high similarity in structure between the  penile corpus cavernosum  and nasal erectile tissue, PDE-5 inhibitors targeting on corpus cavernosum smooth muscle will also act on nasal erectile tissues, which are mainly located at the  inferior turbinate , the  middle turbinate  and  nasal septum . Hence, specific nasal areas may become congested. This mediates inflammatory responses in the  eustachian tube  which connects to the  middle ear , causing an impact on middle ear pressure. Such events will eventually lead to sudden hearing loss. [ 24 ]


Antimalarial drugs  can be classified into several classes based on different mechanisms of action and effects, including quinoline-type drugs,  naphthoquinone ,  antifolates , guanidine derived drugs,  sesquiterpene lactones , etc. In particular, quinoline-type drugs are known to be ototoxic. Examples include  chloroquine  and  hydroxychloroquine  which are quinine-like. Apart from antimalarial effects, these drugs are also used in the treatment of other diseases such as  dermatological , immunological,  rheumatological , and severe infectious diseases. [ 25 ]


Various ototoxic effects are manifested by using antimalarial drugs, with dizziness being one of the most common one. Other effects include vestibular symptoms,  hearing loss  and  tinnitus , which can appear to be both temporary or permanent. [ 25 ]  Nonetheless, the underlying mechanisms of antimalarial-induced ototoxicity are still poorly understood. Studies have suggested that high doses of quinine have an impact on the central auditory pathway and auditory periphery, which leads to elongation and subsequent contraction of isolated OHCs in the  cochlea . This structural alteration affects their functions and results in cochlear blood flow reduction.


Loop diuretics  is a major class of  diuretic drugs  indicated for  oedema  due to  heart failure ,  liver disease  and  kidney disease . It is also used for treating  hypertension . [ 26 ]  Common examples include  furosemide ,  bumetanide  and  ethacrynic acid . Loop diuretics act on the thick ascending limb of the  loop of Henle  in the kidney nephrons. The major mechanism of ion reabsorption in the thick ascending limb is the active transport of ions through  Na + -K + -2Cl −  co-transporters (NKCCs) . By binding to and inhibiting NKCCs at the apical membrane of the  loop of Henle , the reabsorption of Na+, K+ and Cl- is impaired, contributing to a higher ion concentration in the lumen. [ 26 ]  Hence, the ultimate effect of loop diuretics is a reduction in salt reabsorption and an increase in water excretion.


Loop diuretics -induced ototoxicity is suggested to be associated with their action on  stria vascularis  located on the lateral wall of the cochlea. This area is responsible for maintaining the balance of ions of  endolymph . A high potassium concentration as well as a low sodium concentration should be maintained in the  endolymph  to allow cochlear  hair cells  to function normally. [ 27 ]  As the inhibitory actions of loop diuretics will also target on NKCCs existing on membrane surfaces of  stria vascularis  marginal cells, there will be a disturbance on the ionic composition of  endolymph . [ 28 ]  Once the  endocochlear potential  cannot be maintained, hearing is temporarily impaired. It is noticed that the risk of ototoxicity caused by  furosemide  is much higher than that of  bumetanide .


Several approaches can be considered in managing patients who developed ototoxicity as an adverse reaction to the medications. One approach to managing ototoxicity is the use of otoprotective agents. An example is  sodium thiosulfate , which the  US FDA  approved in 2022 to minimise the risk of ototoxicity and hearing loss in newborn, child, and adolescent cancer patients receiving cisplatin. [ 29 ] [ 30 ] [ 31 ]  Other agents being investigated for their potential to reduce ototoxicity include  D-methionine  and  L-N-acetylcysteine . [ 3 ]  The use of D-methionine to protect against hearing loss induced by drugs like cisplatin and aminoglycosides is preliminarily supported by animal studies. [ 32 ]   NMDA antagonists  are also shown to limit aminoglycoside-induced ototoxicity. [ 33 ]


Restorative care, which aims to regenerate hair cells that are damaged by ototoxic drugs, can also be considered. For example, the infusion of neurotrophic factors ( neurotrophin-3 ) was shown to produce otoprotective effects. [ 34 ]  This protective agent was also found to be associated with the survival of cochlear  spiral ganglion neurones  after hearing loss or deafness. [ 35 ]


Audiological management can be implemented, for example, by providing  hearing aids . In more seriously affected patients,  cochlear implantation  may be considered and discussed with the patient. It is also important for the healthcare team to educate affected patients and their family members on  communication skills  in order to minimise the impact on patients’ daily life. [ 3 ]


Paradoxical disinhibition  is a  paradoxical reaction , an uncommon but recognized phenomenon, characterized by acute  excitement  and an altered  mental state , caused by  benzodiazepines . The mechanism is poorly known, but the most accepted theory is that it occurs secondary
to inhibition of the restraining influences of the  cortex  and  frontal lobe  due to the GABA-mimetic action of  benzodiazepines . [ 1 ]  Reversal of this action could be attained by an  NMDA-receptor   antagonist ,  ketamine . [ 2 ]


It is thought that blockage of presynasptic GABA receptors of GABAergic neurons induce stimulation as a net effect, because the action of the most powerful inhibitory  neurotransmitter ,  GABA , is blocked. [ 3 ]


A  paradoxical reaction  (or  paradoxical effect ) is an effect of a  chemical substance , such as a  medical drug , that is opposite to what would usually be expected. An example of a paradoxical reaction is  pain  caused by a  pain relief medication .


Amphetamines  are a class of  psychoactive drugs  that are  stimulants . Paradoxical drowsiness can sometimes occur in adults. [ 1 ]  Research from the 1980s popularized the belief that ADHD stimulants such as amphetamine have a calming effect in individuals with ADHD, but opposite effects in the general population. [ 2 ]  Research in the early 2000s, however, disputes this claim, suggesting that ADHD stimulants have similar effects in adults with and without ADHD. [ 3 ] [ 4 ]


The paradoxical effect or  Eagle effect  (named after  Harry Eagle , who first described it) refers to an observation of an increase in survivors, seen when testing the activity of an  antimicrobial  agent. [ 5 ]  Initially when an  antibiotic  agent is added to a culture media, the number of  bacteria  that survive drops, as one would expect. But after increasing the concentration beyond a certain point, the number of bacteria that survive, paradoxically, increases. [ citation needed ]


In a minority of cases,  antidepressants  can lead to violent  thoughts of suicide or self-harm , as observed in some patients during and after treatment, which is in marked contrast to their intended effect. [ 6 ]  A 1991 study found that children and adolescents were more sensitive to paradoxical reactions of self-harm and suicidal ideation while taking  fluoxetine  (commonly known as Prozac). [ 7 ]  This can be regarded as a paradoxical reaction but, especially in the case of suicide, may in at least some cases be merely due to differing rates of effect with respect to different symptoms of depression: If generalized overinhibition of a patient's actions enters remission before that patient's dysphoria does and if the patient was already suicidal but too depressed to act on their inclinations, the patient may find themself in the situation of being both still dysphoric enough to want to commit suicide but newly free of endogenous barriers against doing so. [ citation needed ]


Chlorpromazine , an  antipsychotic  and  antiemetic  drug which is classed as a "major"  tranquilizer , may cause paradoxical effects such as agitation, hallucinations, excitement, insomnia, bizarre dreams, aggravation of psychotic symptoms and toxic confusional states. [ 8 ]


These may be more common in elderly dementia patients. The apparent worsening of  dementia  may be due to the  anticholinergic  side effects of many antipsychotics. [ 9 ]


Phenobarbital  can cause hyperactivity in children. This may follow after a small dose of 20 mg, on condition of no phenobarbital administered in previous days. [ 10 ]  Prerequisite for this reaction is a continued sense of tension. The mechanism of action is not known, but it may be started by the anxiolytic action of the phenobarbital. [ citation needed ]


Barbiturates  such as  pentobarbital  have been shown to cause paradoxical hyperactivity in an estimated 1% of children, who display symptoms similar to the hyperactive-impulsive subtype of  attention deficit hyperactivity disorder . Intravenous  caffeine  administration can return these patients' behavior to baseline levels. [ 11 ]  Some case reports postulate a high rate (10-20%) of paradoxical response to anesthesia in ADHD patients, though this has not been objectively corroborated in controlled studies. [ 12 ]


Benzodiazepines , a class of psychoactive drugs called the "minor"  tranquilizers , have varying  hypnotic ,  sedative ,  anxiolytic ,  anticonvulsant , and  muscle relaxing  properties, but they may create the exact opposite effects. Susceptible individuals may respond to benzodiazepine treatment with an increase in  anxiety ,  aggressiveness ,  agitation ,  confusion ,  disinhibition , loss of  impulse control ,  talkativeness ,  violent  behavior, and even  convulsions . Paradoxical adverse effects may even lead to  criminal behavior . [ 13 ]  Severe behavioral changes resulting from benzodiazepines have been reported including  mania ,  hypomania ,  psychosis , anger and impulsivity. [ 14 ]


Paradoxical rage reactions due to benzodiazepines occur as a result of an altered level of consciousness, which generates  automatic behaviors ,  anterograde amnesia  and uninhibited aggression. These aggressive reactions may be caused by a disinhibiting  serotonergic  mechanism. [ 15 ]


Paradoxical effects of benzodiazepines appear to be dose-related, that is, likelier to occur with higher doses. [ 16 ]


In a letter to the  British Medical Journal , it was reported that a high proportion of parents referred for actual or threatened  child abuse  were taking medication at the time, often a combination of  benzodiazepines  and  tricyclic antidepressants . Many mothers described that instead of feeling less anxious or depressed, they became more hostile and openly aggressive towards the child as well as to other family members while consuming tranquilizers. The author warned that environmental or social stresses such as difficulty coping with a crying baby combined with the effects of tranquilizers may precipitate a child abuse event. [ 17 ]


Self-aggression  has been reported and also demonstrated in laboratory conditions in a clinical study. Diazepam was found to increase people's willingness to harm themselves. [ 18 ]


Benzodiazepines can sometimes cause a paradoxical worsening of  EEG  readings in patients with seizure disorders. [ 19 ]


Caffeine  is believed by many to cause paradoxical calmness or sedation in individuals with ADHD. [ 20 ]  There is insufficient evidence to determine if sedation caused by caffeine is due to a true paradoxical reaction, or rather from dehydration and sleep deprivation caused by the caffeine. [ 21 ]  Furthermore, there are no conclusive studies showing a differential effect of caffeine in individuals with ADHD compared to the general population.


Naltrexone  blocks the opioid receptors, acting opposite to most opioid pain medications. [ 22 ]  It can be used to negate the effects of opioid painkillers. At doses around one-tenth of the typical dose, naltrexone has been used for pain relief.  Low-dose naltrexone  is believed to have an anti-inflammatory effect. This is an off-label use and not widely accepted by the medical and scientific community. [ 23 ]


Diphenhydramine  (often referred to by the trade name  Benadryl ) is an  anticholinergic   antihistamine  medicine commonly used to treat allergic reactions and symptoms of a  common cold , such as  coughing . Its central antihistaminergic properties also cause it to act as a  sedative , and for this reason it is also used to treat  insomnia . [ 24 ]  Diphenhydramine is also used off-label for its sedative properties, particularly by parents seeking to make their children sedated or sleep during  long-haul flights . This use of diphenhydramine has been criticized for a number of reasons, ranging from ethical to safety concerns, [ 25 ]  but also due to the risk of diphenhydramine's paradoxical reaction, which induces hyperactivity and  irritability . [ 26 ]  This phenomenon can also be observed in adults who use the medication as a sleep aid. The prevalence of this paradoxical reaction is unknown, but research into the phenomenon suggests that it may be as a result of the medicine's interactions with the  CYP2D6 enzyme , and that a  metabolite  of diphenhydramine may be to blame. [ 27 ]


The mechanism of a paradoxical reaction has as yet (2019) not been fully clarified, in no small part due to the fact that signal transfer of single  neurons  in  subcortical  areas of the human brain is usually not accessible. [ citation needed ]


There are, however, multiple indications that paradoxical reactions upon – for example – benzodiazepines, barbiturates,  inhalational anesthetics ,  propofol ,  neurosteroids , and  alcohol  are associated with structural deviations of  GABA A  receptors . The combination of the five subunits of the receptor (see image) can be altered in such a way that for example, the receptor's response to GABA remains unchanged but the response to one of the named substances is dramatically different from the normal one. [ citation needed ]


Pharmaceutical medicine  is a medical discipline concerned with the discovery, evaluation, registration, monitoring and clinical aspects of pharmaceutical development. [ 1 ] [ 2 ] [ 3 ]  All medical specialties overlap to some extent, and likewise the boundaries of pharmaceutical medicine are elastic.  But, at its centre is the clinical testing of medicines, translation of pharmaceutical drug research into new medicines, safety and well-being of patients and research participants in  clinical trials , and understanding the safety profile of medicines and their benefit-risk balance. Pharmaceutical physicians work in the  pharmaceutical industry , universities / medical schools, drug regulatory authorities and  contract research organisations , but have a close affinity with their medical colleagues elsewhere.


As a postgraduate medical discipline, pharmaceutical medicine has a recognised international syllabus, training courses with examinations and qualifications, its own research methodologies, professional bodies and academic societies, journals [ 4 ]  and texts, and embraces new technologies and regulations in pursuit of proof of efficacy, safety and effectiveness of medicines.


Pharmaceutical medicine is a listed medical specialty in the UK, [ 5 ]  Ireland, Switzerland, [ 6 ]  Mexico [ 7 ]  and Belgium. [ 8 ]  This official recognition is underlined by the availability of accredited education and training of specialist pharmaceutical physicians and the establishment and maintenance of standards of practice and professionalism in the competency, care and conduct applied to their work and of growing public recognition and accountability. In the UK, the  Faculty of Pharmaceutical Medicine  of the  Royal College of Physicians  provides accreditation for the specialty.


The basics of pharmaceutical medicine are founded in clinical pharmacology. In addition to expertise in basic research,  drug development , and the structure and function of clinical trials, pharmaceutical physicians must possess a thorough understanding of  pharmacoeconomics , medical aspects of the marketing pharmaceuticals, and business administration, and public health [ 9 ]


Entry-level jobs with this qualification are often clinical research-related. At the entry level, PMST specialists often place into clinical research associate, clinical research analyst, pharmacodynamic data observer, clinical research project manager, drugs and pharmaceutical control manager in clinical research project, etc.


A  Pharmaceutical Physician  is a  healthcare professional , usually a medical physician, who works in  drug development . They work in biotechnology companies, Contract Research Organisations (CROs), Regulatory Authorities, [ 1 ]  and pharmaceutical companies. [ 2 ]


Pharmaceutical physicians are key players in the development and lifecycle management of medicines, acting as crucial intermediaries between science, medicine, and regulatory frameworks. Their primary responsibility lies in overseeing the safe and effective development of new drugs, as well as investigating new uses for existing medications or medical devices. They engage extensively with a wide array of stakeholders, including pharmaceutical and biotech companies, CROs, government agencies, regulatory bodies, scientific communities, and patient organizations. The overarching goal of these collaborations is to bring innovative and promising therapies from the research lab to the market or to extend the use of already-approved drugs to new medical indications.  [ 3 ]


Pharmaceutical physicians contribute to the design, conduct, and monitoring of clinical trials. They work closely with sponsors—often large pharmaceutical companies or biotech firms—who fund these trials. In their regulatory role, they collaborate with agencies like the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or other competent authorities in different jurisdictions. These physicians help navigate the complex regulatory processes necessary to obtain market approval for new therapies, ensuring that trials meet stringent scientific, ethical, and safety standards.


In addition to regulatory guidance, pharmaceutical physicians often lead clinical development teams, shaping the medical strategy for drug development. They may occupy various senior roles within companies, such as Chief Medical Officer (CMO), Medical Director, Clinical Development Physician, or Clinical Research Physician. In these roles, they not only oversee clinical trial phases but also ensure compliance with legal and safety standards while balancing commercial considerations and ensuring a return on investment for sponsors. Their tasks range from working on early-stage drug discovery to post-market safety monitoring and the medical aspects of product marketing.


Pharmaceutical Medicine as a Specialty
Pharmaceutical medicine, a lesser-known yet vital medical specialty, deals with the discovery, development, evaluation, licensing, and marketing of medicinal products. It officially became a recognized specialty in the UK in 2002 under the Faculty of Pharmaceutical Medicine (FPM) of the Royal College of Physicians. The specialty has grown rapidly and is now global, with a significant number of professionals working outside the UK, reflecting the international nature of the pharmaceutical industry.


Training in pharmaceutical medicine usually involves a blend of on-the-job experience and formal education, such as obtaining the Diploma in Pharmaceutical Medicine. Over a four-year training period, pharmaceutical physicians acquire expertise in various areas, including regulatory affairs, pharmacology, drug safety, clinical development, and the healthcare marketplace.


Bringing Drugs to Market
One of the primary roles of a pharmaceutical physician is to shepherd new drugs through the clinical trial process, from initial concept to market. This involves several phases of clinical testing to demonstrate a drug's safety and efficacy before it can be submitted for regulatory approval. Pharmaceutical physicians ensure that these trials meet ethical and scientific standards (in accordance with National and regional Good Clinical Practice and other applicable Clinical Trial Directives and Regulations) while navigating the logistical and regulatory hurdles involved in bringing new therapies to market. Additionally, they may conduct trials to explore new indications for existing medications through various regulatory procedures, expanding their use for different diseases or patient populations.


In summary, pharmaceutical physicians play a critical role in drug development by engaging a range of stakeholders—from regulatory bodies and industry sponsors to CROs and patient groups—to bring innovative therapies to market or explore new uses for existing treatments. Their diverse roles within companies, ranging from clinical research to medical strategy, highlight their vital position at the intersection of medicine, science, and industry.


Pharmaceutical physicians were first recruited after the second World War to fluctuate medical aspects of drug development. British Association of Pharmaceutical Physicians was the first industry composed of pharmaceutical physicians. It was created in 1957 in  Britain . [ 4 ]


Pharmacotherapy , also known as  pharmacological therapy  or drug therapy, is defined as medical treatment that utilizes one or more pharmaceutical drugs to improve ongoing symptoms (symptomatic relief), treat the underlying condition, or act as a prevention for other diseases ( prophylaxis ). [ 1 ]


It can be distinguished from therapy using  surgery  (surgical therapy), radiation ( radiation therapy ), movement ( physical therapy ), or other modes. Among  physicians , sometimes the term  medical therapy   refers specifically  to pharmacotherapy as opposed to surgical or other therapy; for example, in  oncology , medical oncology is thus distinguished from  surgical oncology .


Today's pharmacological therapy has evolved from a long history of medication use, and it has changed most rapidly in the last century due to advancements in  drug discovery . The therapy is administered and adjusted by healthcare professionals according to the  evidence-based guidelines  and the patient's health condition.  Personalized medicine  also plays a crucial role in pharmacological therapy.  Personalized medicine , or precision medicine, takes account of the patient's  genetic variation , liver function, kidney function, etc, to provide a tailor-made treatment for a patient. In pharmacological therapy, pharmacists will also consider  medication compliance .  Medication compliance , or medication adherence, is defined as the degree to which the patient follows the therapy that is recommended by the healthcare professionals. [ 2 ]


The use of medicinal substances can be traced back to 4000 BC in the  Sumer  civilization. [ 3 ]  Healers at the time (called  apothecaries ), for example, understood the application of  opium  for pain relief. [ 4 ]  The history of natural remedies can also be found in other cultures, including  traditional Chinese medicine  in China and  Ayurvedic medicine  in India, which are still in use nowadays. [ 5 ]   Dioscorides , a 1st -century Greek surgeon, described more than six hundred animals, plants, and their derivatives in his medical botany, which remained the most influential pharmacopeia for fourteen hundred years. [ 6 ]  Besides substances derived from living organisms, metals, including  copper ,  mercury , and  antimony , were also used as medical therapies. [ 6 ]  They were said to cure various diseases during the late  Renaissance . In 1657,  tartar emetic , which is an antimony compound, was credited with curing  Louis XIV  of  typhoid fever . [ 6 ]  The drug was also administered intravenously for the treatment of  schistosomiasis  in the 20th century. [ 7 ]  However, due to the concern over acute and chronic antimony poisoning, the role of tartar emetic as an antischistosomal agent was gradually replaced after the advent of  praziquantel . [ 7 ]


Other than using natural products, humans also learned to compound medicine by themselves. The first pharmaceutical text was found on clay tablets from the  Mesopotamians , who lived around 2100 BC. [ 5 ]  Later in the 2nd century AD, compounding was formally introduced by  Galen  as “a process of mixing two or more medicines to meet the individual needs of a patient”. [ 5 ]  Initially, compounding was only done by individual pharmacists, but in the post-World War II period, pharmaceutical manufacturers surged in number and took over the role of making medicine. [ 3 ]  Meanwhile, there was a marked increase in pharmaceutical research, which led to a growing number of new drugs. [ 3 ]  Most drug discovery milestones were made in the last hundred years, from  antibiotics  to  biologics , [ 5 ]  contributing to the foundation of current pharmacological therapy.