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1 CNS PHARMACOLOGY The CNS [brain and spinal cord (SC)] can be divided into its anatomical areas or its physiological functions, both of which our knowledge base of the entire system is not complete. The study of the drugs that can affect the brain and their varied mechanisms of action (MOA) compounds the complexity of this system. CENTRAL NEUROTRANSMITTERS Neurotransmitters are chemical mediators which are released from nerve endings into the synaptic cleft once an action potential has been reached eliciting an influx of Ca++ ions (a voltage dependent action). The neurotransmitter then reaches it target postsynaptic receptor site with the result being either direct excitation or inhibition or enhancing excitation or inhibition. 1. Biogenic amines: a. dopamine-precursor of norepinephrine. Approximately ½ of CNS content of catecholamines is dopamine with large amounts in the basal ganglia (esp. caudate nucleus), olfactory tubercle, central nucleus of the amygdala, limbic system, and certain areas of the frontal cortex. There are 5 dopamine receptor subtypes: D1 (and D5) activate adenylyl cylclase, D2 (and D3 & D4) inhibit adenylyl cyclase. Some D2 receptors may also suppress Ca++ currents and activate K+ currents. 2 b.norepinephrine-relatively large amounts are located in hypothalamus and in certain zones of the limbic system (parts of amygdale & hippocampus) but is present in most brain regions (cerebral cortex, brain stem, cerebellum, and spinal cord) but in lower amounts. It is primarily an excitatory neurotransmitter but in selected areas in the CNS & PNS it has inhibitory effects. c. epinephrine-epi containing neurons are found in medullary reticular formation with some connections to the pontine region, diencephalic nuclei, and paraventricular nucleus of the dorsal thalamus. Also found in periaqueductal gray area and spinal cord. d. serotonin (5-hydroxytryptamine or 5-HT)-is primarily an inhibitory neurotransmitter. Is found in hypothalamus, limbic system, cerebellum, piriform cortex, cerebral cortex, choroids plexus, and retina. It is found in the highest concentration in platelets and the GI tract. There are 14 receptor subtypes each of which is composed of a further set of sybtypes. e. histamine-most of histamine receptors are found in ventral posterior hypothalamus and extends to ascending and descending tracts in the brain. The histamine system is thought to function in regulating arousal, body temperature, vascular dynamics, the reticular activating system. There are 3 histamine receptor subtypes. 2. acetylcholine-seems to be an excitatory transmitter in the CNS vs. its inhibitory effects in the PNS. 3 3. amino acids-most common inhibitory and excitatory neurotransmitters in CNS. a. gamma-aminobutyric acid (GABA)-is major inhibitory mediator in brain with cells containing GABA are some neurons in basal ganglia, cerebellar Purkinje, cerebral cortex, and certain interneurons in spinal cord. There are two subtypes of GABA: GABA-A (a ligand-gated Cl- channel) and GABA-B (a G-protein coupled receptor). b. glycine-inhibitory transmitter released by brainstem and interneurons in spinal cord. c. glutamate-major excitatory neurotransmitter found in cerebral cortex and brain stem. d. aspartate-an excitatory neurotransmitter found in the visual cortex. 4. neuropeptides (polypeptides) a. substance P b. vasopressin c. oxytocin d. somatostatin e. glucagons f. angiotensin II g. atrial natriuretic peptide h. enkephalins i. endorphins 4 5. purine nucleotides a. adenosine b. ATP ACTIONS OF DRUGS IN THE CNS A. The structural and functional properties of neurons and their specific receptors provides a means to modify CNS function, either specifically or generally, by administering drugs that can act at defined receptor sites, either causing inhibition or excitation at the receptor. Drugs that act within the CNS include anticonvulsants, antiparkinsonian agents, opiod & nonopiod analgesics, antiemetics, antipyretics, antidepressants, anypsychotic & antimanic agents, and sedatives & hypnotics. The drugs that selectively modify CNS function act either specifically or nonspecifically according to its effect or response. For example, the effect of the drug is specific when it binds to a target cell’s receptors and affects an identifiable intracellular mechanism and imparts a specific therapeutic action. (These include all the drug categories listed above.) A drug is considered nonspecific if it produces effects on many different target cells and results in diverse molecular mechanisms. The nonspecific drugs are classified according to whether they produce behavioral depression or stimulation. Examples of nonspecific CNS depressants include the anesthetic gases, ethanol, and some hypnoticssedatives. Example of nonspecific CNS stimulants are caffeine and amphetamines. 5 The specific drugs affecting the CNS include the psychotropic drugs which are utilized to correct the “pathological”aspects of the CNS. The four primary categories include the antidepressants, antipsychotics (neuroleptic), antimanic drugs, and antianxiety drugs. It was previously recommended to discontinue certain classes of these drugs, i.e. TCAs and MAOIs, approximately two weeks before surgery; however it is now recommended to continue these medications as the discontinuation of these medications before surgery could possibly increases the risk of the patient developing suicidal ideation or psychotic disturbances. As well, it has been determined that the patient can safely undergo anesthesia and surgery while currently taking these medications. 6 CNS Stimulants Central Nervous System Stimulation -primary action of a diverse group of pharmacological agents -adverse effect associated with many drugs. Behavioral Manifestations of CNS Stimulation -mild elevation in alertness, decrease in drowsiness and lessening of fatigue (Analeptic Effect) -increased nervousness and anxiety -convulsions. Molecular Basis of CNS Stimulation Imbalance between inhibitory and excitatory processes as in the brain. This hyper-excitability of neurons results from: * potentiation or enhancement of excitatory neurotransmission(e.g. amphetamine) * depression or antagonism of inhibitory transmission (e.g. Strychnine) presynaptic control of neurotransmitter release (e.g. picrotoxin) Classification of CNS Stimulants 1-Analeptic Stimulants 2-Respiratory Stimulants 3-Convulsants 4-Psychomotor Stimulant 5-Sympathomimetics or Adrenergic CNS Stimulants 6-Methylxanthines 7 Analeptic Stimulants diverse chemical class of agents majority can be absorbed orally have a short duration of action – primary expression of pharmacological effect is convulsions (tonicclonic) uncoordinated pharmacological effect is terminated through hepatic metabolism Possible Common Mechanism of Action -ability to alter movement of chloride ions across neuronal membranes Therapeutic Uses Group as a whole has limited therapeutic use. Doxapram and Nikithamide - used to counteract postanesthetic respiratory depression and for acute hypercapnia in chronic pulmonary disease. Pentylenetetrazole - used clinically as a tool for screening latent epileptics and experimentally to screen compounds for anti-epileptic activity. Picrotoxin - used to study CNS mechanisms; it interferes with pathways that are strychnine resistant. Strychnine is a source of accidental poisoning. Also used to study CNS mechanism because of its relatively specific action as a glycine antagonist. Adverse Reactions: Convulsion is characterized by opisthotonos, i.e., tonic extension of body and all limbs. Back is arched and only the back of the head and the heels are touching the touching the surface. All 8 sensory stimuli produce exaggerated response and slight sensory stimulation may trigger convulsion. Treatment of Strychnine Poisoning (1) Remove/reduce external sensory stimuli (2) Diazepam or Clonazepam I.V. or nitrous oxide by inhalation to depress CNS and stop convulsions which can be fatal PSYCHOMOTOR STIMULANTS Drugs of Primary Importance Amphetamine - prototype Methamphetamine Methylphenidate CHARACTERISTICS all compounds are absorbed well orally large portion of untransformed amphetamine is excreted unchanged in the urine. Consequently, acidifying the urine with ammonium chloride hastens its clearance, and thus reduces its reabsorption in the renal tubules. Overdose: hyperreflexia, tremors and convulsions Fatalities: hyperthermia rather than cardiovascular effects Pharmacological Actions The primary effects of an oral dose are wakefulness, alertness, decrease fatigue; mood elevation, increased ability to concentrate; an increase in motor and speech activity. Amphetamines also diminish the awareness of fatigue; person may push exertion to the point of severe damage or even death. 9 Stimulate the respiratory center, especially when respiration is depressed by centrally acting drugs, (barbiturates and alcohol). Amphetamine can reverse the marked sedation and behavioral retardation resulting from reserpine-like drug. Depresses appetite by their action on the lateral hypothalamus rather than an effect on metabolic rate. Mechanisms of Action Releases monoamines at synapses in the brain and spinal cord. Inhibits neuronal uptake of monoamine Direct agonist of DA and 5-HT receptors Antagonist at certain adrenreceptors May inhibit monoamine oxidase. Therapeutic Uses Hyperkinesias - Methylphenidate Narcolepsy - Amphetamine or methylphenidate Obesity - Fenfluramine Adverse Effects CNS: Euphoria, dizziness, tremor, irritability, insomnia, Convulsion (at higher doses), hyperthermia and coma C.V. Cardiac stimulation leads to headache, palpitations, cardiac arrhythmias, anginal pain Other: Weight loss, Psychotic Reaction which are often misdiagnosed as schizophrenia. Addiction - including psychic dependence, tolerance and physical dependence. 10 Drug Interactions: Tricyclic antidepressant Antihypertensive Agents Foods high in tyramine content METHYLXANTINES Caffeine: Coffee (100-150 mg/cup) Tea (30-40 mg/cups) Cocoa (15-18mg/cup) Theophylline: Tea and cocoa Theobromine: Cocoa Mechanisms of Action Increase cyclic nucleotide concentration Blocks adenosine receptors Alters intracellular calcium distribution Caffeine, the most widely used drug in the world, is a stimulant. Commonly found in coffee, tea, soft drinks, chocolate and a wide variety of over-the-counter medications, it is legal to buy and easily accessible. Caffeine is a physically addictive drug Pharmacological Activity/ Adverse Effects Low Doses: 50-250mg/Caffeine (Oral Doses) Increase mental alertness, decrease drowsiness Lessen fatigue 11 Larger Doses: 250-600mg/Caffeine Irritability, restlessness, tremor, insomnia, headache, palpitations and hyperesthesia GIT upset Large Doses: > 1000 mg Overt excitement, delirium and clonic seizures Cardiovascular System: Increase rate and force of the heart by directly stimulating myocardium (low doses) Tachycardia and arrhythmias at higher doses. Peripheral vasodilation decease in blood pressure (acute administration) Hypotension and cardiac arrest (rapid i.v. theophyline) Smooth Muscles: Relaxes vascular smooth muscle (Theophylline »Caffeine) Kidney: All xanthines are capable of producing some degree of diuresis in humans (Theophylline > Caffeine) Miscellaneous: Xanthines shorten clotting time by increasing tissue prothrombin and factor V. Adverse effects Stimulate gastric secretions in patients with ulcer Dehydration in children due to vomiting and transient diuretic action (theophyline) Allergic reaction (aminophylline) Psychic Dependence (Caffeine) Therapeutic Uses Caffeine + plus ergot alkaloid (Ergotamine): used to treat migraine headaches 12 OTC preparations: Theophylline: Prophylaxis for chronic asthma Respiratory Stimulant Bronchodilator for relief of asthmatic symptoms NICOTINE CNS Effects: Powerful CNS stimulant at lower doses; Large doses produce clonic convulsion, then depress CNS, compounding postictal depression Stimulates respiration Produces emesis Tolerance to central actions with chronic use Cardiovascular Effects Tachycardia Increased blood pressure Pupillary constriction Cardiovascular collapse - due to CNS depression Ganglionic blockade and arrhythmias Fatalities: Due to respiratory failure COCAINE Psychomotor stimulant local anesthetic Chemistry- alkaloid from coca plant alkaloid is highly lipid-soluble hydrochloride salt is water soluble Routes of Administration Chewing: with an-alkaloid material (South America) 13 Sniffing: hydrochloride salt -absorption: nasal mucous membranes local vasoconstriction slows absorption and prolongs effect Oral: large doses are needed for effect rapid onset Smoking: cocaine is converted to alkaloid (freebase or "crack") which is readily volatilized undegraded at lower temperature. I.V. and smoking: reaches CNS in seconds in high concentration produces more immediate and intense effects Pharmacokinetics large vol. of distribution quickly metabolized: half-life 30-90 minutes principal metabolites: a) Ecogonine methylester - inactive b) Benzoylecogonine - inactive c) norcocaine - active half lives of metabolites: 4 to 6 hrs. - metabolites: Excreted in urine Drug Testing: BE - detectable for 1-3 days for a few hours Cocaine - detectable 14 Drug addiction Drug addiction is widely considered a pathological state. The disorder of addiction involves the progression of acute drug use to the development of drug-seeking behavior, the vulnerability to relapse, and the decreased, slowed ability to respond to naturally rewarding stimuli. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) has categorized three stages of addiction: preoccupation/anticipation, binge/intoxication, and withdrawal/negative affect. These stages are characterized, respectively, everywhere by constant cravings and preoccupation with obtaining the substance; using more of the substance than necessary to experience the intoxicating effects; and experiencing tolerance, withdrawal symptoms, and decreased motivation for normal life activities. By the American Society of Addiction Medicine definition, drug addiction differs from drug dependence and drug tolerance. Drugs causing addiction Drugs known to cause addiction include illegal drugs as well as prescription or over-the-counter drugs, according to the definition of the American Society of Addiction Medicine. Stimulants: o Amphetamine and Methamphetamine o Caffeine o Cocaine o Nicotine Sedatives and Hypnotics: o Alcohol 15 o Barbiturates o Benzodiazepines, particularly alprazolam, clonazepam, temazepam, and nimetazepam o Methaqualone and the related quinazolinone sedativehypnotics Opiate and Opioid analgesics o Morphine and Codeine, the two naturally-occurring opiate analgesics o Semi-synthetic opiates, such as Heroin (Diacetylmorphine), Oxycodone, and Hydromorphone o Fully synthetic opioids, such as Fentanyl and its analogs, Meperidine/Pethidine, and Methadone Addictive drugs also include a large number of substrates that are currently considered to have no medical value and are not available over the counter or by prescription. An article in the Lancet compared the harm and addiction of 20 drugs, using a scale from 0 to 3 for physical addiction, psychological addiction, and pleasure to create a mean score for addiction. Caffeine was not included in the study. The results can be seen in the chart above. Addictive potency The addictive potency of drugs varies from substance to substance, and from individual to individual Drugs such as codeine or alcohol, for instance, typically require many more exposures to addict their users than drugs such as heroin or cocaine. 16 Likewise, a person who is psychologically or genetically predisposed to addiction is much more likely to suffer from it. Although dependency on hallucinogens like LSD ("acid") and psilocybin (key hallucinogen in "magic mushrooms") is listed as Substance-Related Disorder in the DSM-IV, most psychologists do not classify them as addictive drugs. The most common drug addictions are to legal substances such as: Caffeine Nicotine in the form of tobacco, particularly cigarettes Alcohol Individual mechanisms of effect The basic mechanisms by which different substances activate the reward system are as described above, but vary slightly among drug classes. Depressants Depressants such as alcohol and benzodiazepines work by increasing the affinity of the GABA receptor for its ligand; GABA. Narcotics such as morphine and methadone, work by mimicking endorphins—chemicals produced naturally by the body which have effects similar to dopamine— or by disabling the neurons that normally inhibit the release of dopamine in the reward system. These substances (sometimes called "downers") typically facilitate relaxation and pain-relief. Stimulants Stimulants such as amphetamines, nicotine, and cocaine, increase dopamine signaling in the reward system either by directly stimulating its 17 release, or by blocking its absorption (see "reuptake"). These substances (sometimes called "uppers") typically cause heightened alertness and energy. They cause a pleasant feeling in the body, and euphoria, known as a high. This high wears off leaving the user feeling depressed. This sometimes makes them want more of the drug, and can worsen the addiction Treatment Treatments for drug addiction vary widely according to the types of drugs involved, amount of drugs used, duration of the drug addiction, medical complications and the social needs of the individual. Determining the best type of recovery program for an addicted person depends on a number of factors, including: personality, drug(s) of addiction, concept of spirituality or religion, mental or physical illness, and local availability and affordability of programs. Many different ideas circulate regarding what is considered a "successful" outcome in the recovery from addiction. It has widely been established that abstinence from addictive substances is generally accepted as a "successful" outcome, however differences of opinion exist as to the extent of abstinence required. In the USA and in many other countries, the goal of treatment for drug dependence is generally total abstinence from all drugs, which while theoretically the ideal outcome, is in practice often very difficult to achieve. Other countries particularly in Europe argue the aims of treatment for drug dependence to be more complex, with treatment aims including reduction in use to the point that drug use no longer interferes with normal activities such as work and family commitments, shifts away 18 from more dangerous routes of drug administration such as injecting to safer routes such as oral administration, reduction in crime committed by drug addicts, and treatment of other comorbid conditions such as AIDS, hepatitis and mental health disorders. These kind of outcomes can often be achieved without necessarily eliminating drug use completely, and so drug treatment programs in Europe often report more favourable outcomes than those in the USA because the criteria for measuring success can be met even though drug users on the programme may still be using drugs to some extent. The supporters of programs with total abstinence from drugs as a goal stress that enabling further drug use mean prolonged drug use and a risk for an increase of total number of addicts; the participants in the program can introduce new users in the habit. Drug addiction is a complex but treatable brain disease. It is characterized by compulsive drug craving, seeking, and use that persist even in the face of severe adverse consequences. For many people, drug addiction becomes chronic, with relapses possible even after long periods of abstinence. In fact, relapse to drug abuse occurs at rates similar to those for other well-characterized, chronic medical illnesses such as diabetes, hypertension, and asthma. As a chronic, recurring illness, addiction may require repeated treatments to increase the intervals between relapses and diminish their intensity, until abstinence is achieved. Through treatment tailored to individual needs, people with drug addiction can recover and lead productive lives. The ultimate goal of drug addiction treatment is to enable an individual to achieve lasting abstinence, but the immediate goals are to reduce drug abuse, improve the patient's ability to function, and minimize the medical and social complications of drug abuse and addiction. Like people with diabetes or heart disease, people in treatment 19 for drug addiction will need to change behavior to adopt a more healthful lifestyle. Anti-addictive drugs Other forms of treatment include replacement drugs such as methadone or buprenorphine, used as a substitute for illicit opiate drugs Although these drugs are themselves addictive, opioid dependency is often so strong that a way to stabilize levels of opioid needed and a way to gradually reduce the levels of opioid needed are required. In some countries, other opioid derivatives such as levomethadyl acetate, dihydrocodeine, dihydroetorphine and even heroin are used as substitute drugs for illegal street opiates, with different drugs being used depending on the needs of the individual patient. Substitute drugs for other forms of drug dependence have historically been less successful than opioid substitute treatment, but some limited success has been seen with drugs such as dexamphetamine to treat stimulant addiction, and clomethiazole to treat alcohol addictionBromocriptine and desipramine have been reported to be effective for treatment of cocaine but not amphetamine addiction. Other pharmacological treatments for alcohol addiction include drugs like disulfiram, acamprosate and topiramate, but rather than substituting for alcohol, these drugs are intended to reduce the desire to drink, either by directly reducing cravings as with acamprosate and topiramate, or by producing unpleasant effects when alcohol is consumed, as with disulfiram. These drugs can be effective if treatment is maintained, but compliance can be an issue as alcoholic patients often forget to take their medication, or discontinue use because of excessive side effects. [36][37] 20 Additional drugs acting on glutamate neurotransmission such as modafinil, lamotrigine, gabapentin and memantine have also been proposed for use in treating addiction to alcohol and other drugs. Opioid antagonists such as naltrexone and nalmefene have also been used successfully in the treatment of alcohol addiction, which is often particularly challenging to treat. These drugs have also been used to a lesser extent for long-term maintenance treatment of former opiate addicts, but cannot be started until the patient has been abstinent for an extended period, otherwise they can trigger acute opioid withdrawal symptoms. Treatment of stimulant addiction can often be difficult, with substitute drugs often being ineffective, although newer drugs such as nocaine, vanoxerine and modafinil may have more promise in this area, as well as the GABAB agonist baclofen. Another strategy that has recently been successfully trialled used a combination of the benzodiazepine antagonist flumazenil with hydroxyzine and gabapentin for the treatment of methamphetamine addiction. Another area in which drug treatment has been widely used is in the treatment of nicotine addiction. Various drugs have been used for this purpose such as bupropion, mecamylamine and the more recently developed varenicline. The cannaboinoid antagonist rimonabant has also been trialled for treatment of nicotine addiction but has not been widely adopted for this purpose. Ibogaine is a psychoactive drug that specifically interrupts the addictive response, and is currently being studied for its effects upon cocaine, heroin, nicotine, and SSRI addicts. Alternative medicine clinics offering 21 ibogaine treatment have appeared along the U.S. border. Ibogaine treatment for drug addiction can be reasonably effective, but potentially dangerous side effects which have been linked to several deaths have limited its adoption by conventional medical practice. A synthetic analogue of ibogaine, 18-methoxycoronaridine has also been developed which has similar efficacy but less side effects, however this drug is still being tested in animals and human trials have not yet been carried out. [edit] Alternative therapies Alternative therapies, such as acupuncture, are used by some practitioners to alleviate the symptoms of drug addiction. In 1997, the American Medical Association (AMA) was adopted as policy following statement after a report on a number of alternative therapies including acupuncture: There is little evidence to confirm the safety or efficacy of most alternative therapies. Much of the information currently known about these therapies makes it clear that many have not been shown to be efficacious. Well-designed, stringently controlled research should be done to evaluate the efficacy of alternative therapies. Accupuncture has been shown to be no more effective than control treatments in the treatment of opiate dependence. Acupuncture, acupressure, laser therapy and electrostimulation have no demonstrated efficacy for smoking cessation. 22 Medical definitions The terms abuse and addiction have been defined and re-defined over the years. The 1957 World Health Organization (WHO) Expert Committee on Addiction-Producing Drugs defined addiction and habituation as components of drug abuse: Drug addiction is a state of periodic or chronic intoxication produced by the repeated consumption of a drug (natural or synthetic). Its characteristics include: (i) an overpowering desire or need (compulsion) to continue taking the drug and to obtain it by any means; (ii) a tendency to increase the dose; (iii) a psychic (psychological) and generally a physical dependence on the effects of the drug; and (iv) detrimental effects on the individual and on society. Drug habituation (habit) is a condition resulting from the repeated consumption of a drug. Its characteristics include (i) a desire (but not a compulsion) to continue taking the drug for the sense of improved wellbeing which it engenders; (ii) little or no tendency to increase the dose; (iii) some degree of psychic dependence on the effect of the drug, but absence of physical dependence and hence of an abstinence syndrome [withdrawal], and (iv) detrimental effects, if any, primarily on the individual. In 1964, a new WHO committee found these definitions to be inadequate, and suggested using the blanket term "drug dependence": The definition of addiction gained some acceptance, but confusion in the use of the terms addiction and habituation and misuse of the former continued. Further, the list of drugs abused increased in number and diversity. These difficulties have become increasingly apparent and 23 various attempts have been made to find a term that could be applied to drug abuse generally. The component in common appears to be dependence, whether psychic or physical or both. Hence, use of the term 'drug dependence', with a modifying phase linking it to a particular drug type in order to differentiate one class of drugs from another, had been given most careful consideration. The Expert Committee recommends substitution of the term 'drug dependence' for the terms 'drug addiction' and 'drug habituation'. The committee did not clearly define dependence, but did go on to clarify that there was a distinction between physical and psychological ("psychic") dependence. It said that drug abuse was "a state of psychic dependence or physical dependence, or both, on a drug, arising in a person following administration of that drug on a periodic or continued basis." Psychic dependence was defined as a state in which "there is a feeling of satisfaction and psychic drive that requires periodic or continuous administration of the drug to produce pleasure or to avoid discomfort" and all drugs were said to be capable of producing this state: There is scarcely any agent which can be taken into the body to which some individuals will not get a reaction satisfactory or pleasurable to them, persuading them to continue its use even to the point of abuse — that is, to excessive or persistent use beyond medical need. The 1957 and 1964 definitions of addiction, dependence and abuse persist to the present day in medical literature. It should be noted that at this time (2006) the Diagnostic Statistical Manual (DSM IVR) now spells out specific criteria for defining abuse and dependence. (DSM IVR) uses the term substance dependence instead of addiction; a maladaptive pattern of substance abuse, leading to clinically significant impairment or distress, 24 as manifested by three (or more) specified criteria, occurring at any time in the same 12-month period. This definition is also applicable on drugs with smaller or nonexistent physical signs of withdrawal, for ex. cannabis. In 2001, the American Academy of Pain Medicine, the American Pain Society, and the American Society of Addiction Medicine jointly issued "Definitions Related to the Use of Opioids for the Treatment of Pain," which defined the following terms:[3] Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Physical dependence is a state of adaptation that is manifested by a drug class specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist. Tolerance is the body's physical adaptation to a drug: greater amounts of the drug are required over time to achieve the initial effect as the body "gets used to" and adapts to the intake. Pseudo addiction is a term which has been used to describe patient behaviors that may occur when pain is undertreated. Patients with unrelieved pain may become focused on obtaining medications, may “clock watch,” and may otherwise seem inappropriately “drug seeking.” Even such behaviors as illicit drug use and deception can occur in the patient's efforts to obtain relief. Pseudoaddiction can be distinguished 25 from true addiction in that the behaviors resolve when pain is effectively treated. The Diagnostic and Statistical Manual of Mental Disorders, DSM-IV-TR doesn’t use the word addiction at all. Instead it has a section about Substance dependence "When an individual persists in use of alcohol or other drugs despite problems related to use of the substance, substance dependence may be diagnosed. Compulsive and repetitive use may result in tolerance to the effect of the drug and withdrawal symptoms when use is reduced or stopped. This, along with Substance Abuse are considered Substance Use Disorders...." [54] A definition of addiction proposed by professor Nils Bejerot: "An emotional fixation (sentiment) acquired through learning, which intermittently or continually expresses itself in purposeful, stereotyped behavior with the character and force of a natural drive, aiming at a specific pleasure or the avoidance of a specific discomfort." [55] [edit] Addiction and drug control legislation Depending on the jurisdiction, addictive drugs may be legal only as part of a government sponsored study, illegal to use for any purpose, illegal to sell, or even illegal to merely possess. Most countries have legislation which brings various drugs and drug-like substances under the control of licensing systems. Typically this legislation covers any or all of the opiates, amphetamines, cannabinoids, cocaine, barbiturates, hallucinogenics and a variety of more modern 26 synthetic drugs, and unlicensed production, supply or possession is a criminal offence. Usually, however, drug classification under such legislation is not related simply to addictiveness. The substances covered often have very different addictive properties. Some are highly prone to cause physical dependency, whilst others rarely cause any form of compulsive need whatsoever. Also, under legislation specifically about drugs, alcohol is not usually included. Although the legislation may be justifiable on moral or public health grounds, it can make addiction or dependency a much more serious issue for the individual: reliable supplies of a drug become difficult to secure, and the individual becomes vulnerable to both criminal abuse and legal punishment. It is unclear whether laws against drugs do anything to stem usage and dependency. In jurisdictions where addictive drugs are illegal, they are generally supplied by drug dealers, who are often involved with organized crime. Even though the cost of producing most illegal addictive substances is very low, their illegality combined with the addict's need permits the seller to command a premium price, often hundreds of times the production cost. As a result, the addict sometimes turns to crime to support their habit.