EPILEPSY

Epilepsy and antiepileptic drugs: Epilepsy: is a very common chronic disorder characterized by recurrent seizures Seizure: excessive discharge of cortical neuron Convulsion: involuntary contraction of voluntary muscles ** Patients may have epilepsy or seizure disorders without convulsions International classification of seizures 1) Partial "focal": In which the excessive neuronal discharge involves one part of the cortex Seizure activity starts in one part of the brain Main types of partial "focal" seizures: A. Simple: consciousness is preserved (seizure activity while person is alert)

B. Complex: consciousness is impaired (seizure activity with change in awareness of surroundings) 2) Generalized: In which the excessive neuronal discharge involves the whole cortex Seizure activity involves the whole brain Main types of generalized seizures: A. Tonic-clonic (Grand-mal seizures): Composed of two phases: Tonic phase: abrupt loss of consciousness (less than 1 min), epileptic cry, falling, generalized stiffening of body muscles and limbs are back arched Clonic phase:alteration of muscle contraction and relaxation(stiffening and jerking of body & limbs & head muscles) with lip or tongue biting, eyes blinking, fecal & urinary incontinence ** Usually there's a phase after these two phases known as post-ictal confusional fatigue phase where the patient is tired, confused, having lethargy and unaware of what has just happened!!

Absence (petit-mal seizures): *Onset of this type occurs from ages 3-16 years (mainly in children) *Characterized by:altering of consciousness lasting for10-30 seconds when the patient stares and blinks without falling ** After the seizure ends the patient gets back to his/her activity

B. Myoclonic: o Characterized by: single or multiple muscle jerk (jerking movements of the body) C. Tonic D. Atonic o Characterized by: loss of body tone and falling heavily to the ground without any convulsions 3) Status epilepticus: It is a life threatening emergency requiring quick treatment
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In which there's series of seizures without recovery of consciousness between attacks 4) Febrile seizures: Young children (3 months to 5 years) frequently develop seizures with illness accompanied by high fever The cause of these seizures is an infection accompanied with high fever To treat these seizures we should treat the fever (pyrexia) Treatment of choice is: Diazepam which is given rectally ** Diagnosis of specific seizure type is important for prescribing the most appropriate anti-seizure drug (because for each type of seizure we have specific group of drugs) ** Treatment may involve combination of drugs Aim of treatment: Complete suppression of seizures "fits, attacks" and if not possible then, Reduction of seizure frequency "number" as much as possible with minimum and tolerable adverse drug reactions (ADRs) ** Usually, treatment of epilepsy is highly challenging, first of all we should carefully diagnose the type of seizure the patient has based on patient's full description of the seizure type and frequency, then we should select the proper type of drug based on patient's age, drug to drug interaction, liver and kidney function tests, and other factors ** The management of patients with epilepsy is focused on 3 main goals:
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o Improve quality of life o Controlling seizures o Avoiding side effects of anti-seizure drugs ** Anti-seizure drugs are associated with many adverse drug reactions and many drug to drug interactions Etiology of epilepsy: Primary "idiopathic" seizures: These seizure have no identifiable cause ** Some seizures arise secondary to other conditions. However, in most cases, the cause of the seizure is unknown Secondary "symptomatic or acquires" seizures: These seizures occur secondary to an identifiable cause such as: a. b. c. d. e. f. Intracranial neoplasms Infectious diseases, such as: meningitis, influenza High fever (in children) Head trauma Metabolic disorders, such as: hypoglycemia and hypocalcaemia Alcohol or drug withdrawal (sudden stoppage)

Clinical evaluation of epilepsy: History includes an evaluation of the seizure, including interviews of the patients family Laboratory test may also identify an underlying etiology (CBC, Glucose level, Calcium level to detect any metabolic disorder)

 Neurological imaging studies may also identify an underlying etiology (MRI, CT scan to detect any brain neoplasm or injury) EEG "electro-encephalo-gram" studies measure the electrical activity of the brain It is the most important test to diagnose epilepsy (although in some cases it might not be helpful) An EEG is useful for classifying the seizure, but the EEG by itself cannot rule seizures in or out (as there are patients with normal EEGs who have seizure disorders) Normal EEG will NOT exclude epilepsy! As patients have normal EEG between attacks but abnormal EEG during attacks Principles of drug therapy: Seizure control Approximately 50% of epileptics achieve complete seizure control through drug therapy In another 25% of epileptics, drugs reduce the frequency of seizures Epileptics generally require continuous drug therapy for at least 4 seizurefree years before the drug can be discontinued Anti-epileptic drugs are indicated when there is two or more seizures occurred in short interval One seizure doesn't require anti-epileptic drug treatment An initial therapeutic aim is to use only one drug (mono-therapy) Single drug is used initially NOT combination of drugs
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 Before any drug treatment is instituted, remedial causes of the seizure activity should be excluded A single primary drug that is most appropriate for the seizure type must be selected If there is more than one appropriate primary drug, then, age, sex, and compliance of the patient must be considered Additional therapy If seizures recur after the maximal tolerated dose of the primary drug is reached, then, a second drug is added at a low dose The dose of the second drug is increased gradually until an optimal therapeutic level is reached The first drug is maintained until the optimal dose of the second drug is determined; then the first drug is discontinued gradually to avoid triggering seizure activity The sudden withdrawal of drugs should be avoided NOT to trigger unwanted seizure activity Withdrawal of anti-seizure drugs may be considered after seizure-free period of 2-3 or more years Mechanism of action of anti-epileptic drugs: In epilepsy, there's excessive neuronal discharge in the central nervous system which is either partial or generalized, and drugs used to treat epilepsy work by one of these mechanisms: a. Increasing the activity of inhibitory neurotransmitters in the CNS Inhibitory tone by facilitation of GABA-mediated hyperpolarization
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 Drugs increasing inhibition include: barbiturates and benzodiazepines b. Decreasing the activity of excitatory neurotransmitters in the CNS Pre-synaptic Ca influx through type-T channels in thalamic neurons Drugs decreasing excitation include: ethosuximide and valproic acid c. Decreasing the neuronal firing in the CNS by blocking the voltage-gated ion channels Axonal conduction by preventing Na influx through fast Na channels Drugs decreasing neuronal firing include: Carbamazepine, phenytoin and also barbiturates and valproic acid (at high doses) Antiepileptic drugs: 1) Phenytoin: Mechanism of action: blocks voltage-gated sodium channels in neuronal membrane and thus decreasing axonal conduction and firing Clinical uses: partial seizures & generalized tonic-clonic seizures ** Phenytoin is used successfully in the treatment of partial seizures as well as generalized tonic-clonic seizures, but if we use phenytoin in the management of absence seizures then seizures will get worse Phenytoin has narrow therapeutic index(considered as an un-savedrug) Phenytoin is metabolized by zero order kinetics in which the relation between the dose & plasma concentration is not linear
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 So that small increase in drug dose results in rapid increase in plasma concentration and this will increase the risk for drug toxicity Phenytoin has high drug to drug Interactions since it is: a. Highly protein bound drug so that increasing free drug concentration may produce a high toxic effect b. Hepatic enzyme inducer drug so that it will accelerate the metabolism of other drugs ** If phenytoin is the primary drug used to treat seizures, and it was proven that this drug isn't effective to stabilize seizures, then a secondary drug should be used to stabilize the condition, let's say it was Carbamazepine, we should keep in mind that Phenytoin decreases the effectiveness of Carbamazepine since it induces its metabolism Side effects: a. CNS: ataxia, diplopia (double vision), nystagmus (rapid vertical and horizontal eye movement) b. Gingival hyperplasia (especially in children) c. Hairsutism (enhance hair growth) d. Teratogenic effects Phenytoin shouldn't be given during pregnancy (especially in the first trimester) NOT to induce fetal malformation (cleft lip and palate) e. Abnormalities of vitamin D catabolism (leading to bone disorders due to vitamin D deficiency, like: osteomalacia in adults or rickets in children) f. folate levels (leading to megaloblastic anemia) ** Keep in mind that phenytoin side effects are dose related
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2) Carbamazepine: Mechanism of action: blocks voltage-gated sodium channels in neuronal membrane and thus decreasing axonal conduction and firing (same as phenytoin) Clinical uses: partial seizures & generalized tonic-clonic seizures (same as phenytoin)& for non-epileptic disorders such as: Trigeminal Neuralgia & mania & neuropathic pain ** Trigeminal neuralgia is characterized by facial pain due to problems in trigeminal nerve ** Mania ( ) is characterized by mood changes ** Neuropathic pain is commonly encountered in diabetic patients if their condition isn't stabilized Similarities between phenytoin & Carbamazepine: a. Both are hepatic enzyme inducers (both accelerate the metabolism of other drugs) b. Both enhance catabolism of vitamin D (both lead to bone disorders) c. Both cause megaloblastic anemia but more with phenytoin (both decrease folate levels) d. Both are NOT used in treatment of absence seizures Side effects: a. CNS: ataxia and diplopia (double vision) b. Abnormalities of vitamin D catabolism (leading to bone disorders due to vitamin D deficiency, like: osteomalacia in adults or rickets in children) c. folate levels (leading to megaloblastic anemia)
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3) Valproic acid:

Mechanism of action: blocking voltage-gated sodium channels at high doses OR can potentiate the inhibitory effect of GABA OR blocking Tcalcium channel ** Valproic acid is one of the drugs having multiple mechanisms of action ** Valproic acid is one of the drugs having broad anti-seizure effects and can be used for any type of epilepsy

Clinical uses: partial seizures & generalized tonic-clonic seizures & absence seizure & Myoclonic seizures Side effects: a. Alopecia (enhance hair loss) b. Teratogenicity Valproic acid shouldn't be given during pregnancy (especially in the first trimester) NOT to induce fetal malformation c. Liver damage (enhance haptotoxicity) 4) Ethosuximide: Mechanism of action: act by blocking T-calcium channels Clinical uses: The main drug used to treat absence seizures 5) Phenobarbital: It is one type of barbiturates Mechanism of action: blocking voltage-gated sodium channels at high doses OR can potentiate the inhibitory effect of GABA

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 Clinical use: same as phenytoin for partial seizures & generalized Tonic-Clonic seizures & maybe used in the treatment of status epilepticus 6) Benzodiazepines a. Diazepam: given Intravenously to treat status epilepticus b. Clonazepam: to treat absence seizures & Myoclonic seizures Drugs used in seizure disorders: 1) Partial seizures and generalized tonic-clonic seizures Carbamazepine, Phenytoin, Valproic acid and Phenobarbital 2) Absence Seizures Ethosuximide, Valproic acid and Clonazepam 3) Myoclonic Clonazepam and Valproic acid ** There are adjunct newer drugs which aren't used along but in combination with the old drugs ** Newer drugs are highly expensive and have fewer adverse effects Management of status epilepticus: 1) Establish airway, oxygenate, recovery position 2) Establish intravenous access and give intravenous lorazepam 2-4 mg OR intravenous diazepam 5-10 mg OR intravenous midazolam 10 mg ** Lorazepam, Diazepam and Midazolam are Benzodiazepines derivatives ** Don't memorize doses ** Lorazepam is our first drug of choice while diazepam and midazolam are alternatives 3) Check blood for: glucose, urea and electrolytes, Calcium, anticonvulsant levels, and arterial blood gas and pH
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4) If seizures continue, administer intravenous Phenobarbital OR intravenous phenytoin as second-line treatment 5) In sever status epilepticus especially that doesn't respond to these measures, general anaesthesia and neuromuscular blocker (muscle relaxant) and artificial respiration are needed ** It is important that we stop seizures in here because their continuation leads to brain damage

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Opioid Analgesics
- Analgesics: are drug that can relieves (reduce) pain without loss of consciousness , they acting on CNS or peripheral pain mechanism to suppress pain sensation. analgesics including opioids (powerful highly effective pain killer) and NSAIDS(non-steroidal anti-inflammatory drugs) like : aspirin, ibuprofen and voltaren. - Narcotics: they have an analgesic effect(pain relieve) and sedative properties(CNS sedation). - Opioids: include natural ,semi synthetic and synthetic alkaloids that produce a morphine like-effect , their effect can be block by specific(non-selective) opioids antagonist known as Naloxone. Opioids highly use illegally(addiction),they induce psychology, physiology and physical dependence. - Pain: unpleasant sensory and emotional experience associated with actual or potential tissue damage.

- Classification of pain by 1) by onset and duration

Acute pain Chronic pain Sudden in onset persistant or recurrent. - usually subsides once treated - often difficult to treat . 2) Types of pain - Neuropathic pain : the pain due to neuronal damage(nerve damage) in the peripheral tissue or in CNS.
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-Nociceptive pain : result of activation of sensory(afferent)receptors(nociceptors) by mechanical, thermal or chemical stimuli. Functional, physiologic or normal pain. Opioids peptide : are used exogenous but they presented as endogenous opioids, synthesize by nerve cell and adrenal medullary cells and interact with opioid receptors. They can be released to regulate pain sensation and stressful situation or anticipation of pain . Endogenous opoids: endorphins, dynorphines and enkephalines . Opioids receptors : Beginning with their class, usually effector opioids receptor are Gprotein coupled receptor . But the other mechanism that the opioids act on neuron by voltage gated channel, in which they will cause closing of ca2+ channel on presynaptic neuron to inhibit neuronal firing to initiate action potential, on the same time they will cause open K+ channel on postsynaptic neuron .

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You know from the physiology that entrance of Ca is important to enhance neurotransmitters in presynaptic neuron. Opioids can lock through opioid receptor interance of Ca by closing Ca channel in presynaptic neuron, no Ca entrance no releasing of neurotransmitter(excitation). On the same time opioid receptor affect on postsynaptic neuron, they inhance K efflux its mean neuronal inhibition (repolarizing or hypopolarized or neuronal initial) so we can suppressing pain sensation by inhibit formation (propagation) of action potential.

Receptor stimulation : Mu*

P hysical dependence E uphoria
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A nalgesia R espiratory depression

*kappa
S edation A nalgesia (spinal) M iosis

*Delta
A nalgesia (mu), (delta), (kappa) stimulation lead to analgesia. Opioid overdose will depress respiratory system(death).

- Classification of opioids :
1) Natural : morphine - codeine thebaine. 2) Semi synthetic : heroin(diacetylmorphine) it's lipid solubility highr than morphine , heroin rapidly penetrate CNS so rapidly get the ipiod effect (that need by addicted individual). 3) Synthetic : meperidine-methadone-dextromethorphan-fentanylpentazocin.

- Classification : (exam Q)
1) Strong agonists : Ex: morphine methadone fentanyl- meperidine. 2) Moderate agonist:
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Ex: codeine.

3) Mixed agonists-antagonist : Ex : pentazocin.(it can act as agonist and as antagonist depending in which receptor it bind) 4)Antagonist : Ex: Naloxone, used to treat overdose(toxicity) very very imp. *slide 13: the figure isn't to memorize.. To get a powerful analgesic effect we use strong agonist(fentanyl), as much we stimulated receptors as much get analgesic effect . Morphine : morphine and other opioid act through binding to opioid receptors. These receptors distributed in the CNS at regions involved in transmission and modulation of pain. Pharmacological actions : -Strong agonsits - acute effect : 1) Analgesia : can suppress pain sensation without loss of consciousness.
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Visceral pain relieve better than somatic pain. Nociceptive pain is better relieve than neuropathic pain. Degree of analgesia is dose dependent(increase the dose increase the analgesics effect) 2) Euphoria : morphine produces a powerful sense of contiment and well-bieng.(cause of addiction) 3) Sedation, drowsiness and hypnosis . We can get active CNS depressant effect if it's used with CNS depressant. 4) Respiratory depression : inhibits respiratory center in the medulla and decreasing its sensitivity to CO2 (Co2 retention) . it is dose-related . Death from morphine overdose is usually due to respiratory failure. 5) Antitussive : opioid(drug) suppress the dry cough by suppress the cough central in the medulla which control cough reflex . Two types of cough : unproductive(dry or irritant) should be suppressed while productive(sputum and respiratory secretion) cough shouldn't be suppress . Dextromethorphan is one component of low cough , can be used as antitissive , it is safe(very low CNS addiction effect) it can used public (no restriction) . Codeine is a potent inhibitor of the cough reflex.
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Meperidine has a week effect . 6) Miosis : opioid act on (mu)and(kappa) receptors to stimulate oculomotor nucleus to constrict pupil . pin point pupils(very dense smaller pupil-) are characteristics of morphine over dose (opioid addiction) 7) Nausea and vomiting: Stimulation of CTZ. Because it stimulate chemoreceptor trigger zone,and once it stimulated ,its stimulation may initiate vomiting. 8) GIT effects They found that morphine and other opioids can reduce GI motility ,Increases GI tone , by that they reduce gastrointestinal secretion so Produces constipation. 9) Urinary retention: Due to contraction of sphincter, inhibition of reflex of urination and increase ADH release >>>urinary retention. By that we considered morphine and other opioids should not be used in patient with benign prostatic hyperplasia, in which this patient who already complain from urinary retention,so if this patient used opioids the risk will be more. 10) Biliary tract: Morphine is contraindicated in biliary colic because Contraction of biliary muscle and sphincter of Odi Biliary tract spasm Opioids can exacerbate biliary colic . by that opioids will lead excessive pain in colic except morphine. 11) UTERUS: they found that morphine can decrease uterine tone,by that they will be prolong labor >>>so morphine has multiple effect.
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12) SEDATION and have anxiolytic effects. 13) CARDIOVASCULAR SYSTEM : ( no prominent effects). *They found that if the morphine used in a high dose lead to Peripheral vasodilation , most prominent effect due to histamine release and decreased adrenergic tone. *Very high doses of morphine may produce bradycardia . 14) Histamine release: Morphine releases histamine from mast cells, histamine is a neurotransmitter,once the histamine release, will induce bronchoconstriction , vasodilation,(the vasodilation associated with urticaria, sweating, redness). Because it can cause bronchoconstriction, so morphine is contraindicated in patient with bronchial asthma or patient with chronic obstructive pulmonary disease. *** there is something very important about morphine: Morphine suppress respiratory center, increase CO2 retention >>> this will induce cerebral vasodilation >>> this will increase intra cranial pressure(ICP) or cerebrospinal fluid pressure>>>therefore morphine and other opioids is usually contraindicated in patient with acute head injury . Suppose that there is patient with RTA (renal tubular acidosis),come this patient with this injury, he need an analgestic,they found that morphine can increase ICP,so If this patient with head injury(that already has
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increase in ICP) and receive morphine this will increase ICP more and more,by that this will increase the risk of hemorrhage .

actions of Morphine (CNS) contd.

*Depression: 1. respiratory centre depression Both rate and depth of respiration are diminished-( Dangerous in Head injury and asthmatics). 2. suppress Cough Centre 3.supress Vasomotor centre, so they can lead to bradycardia. In high doses can reduce the BP.

*stimulation: 1.CTZ sensitize CTZ to vestibular and other impulses. Why it stimulate the chemo receptor trigger zone ? this will initiate vomiting it stimulate : 2.Edinger Westphal Nucleus (stimulate occulomator nerve will cause miosis ). 3.Vagal centre(if stimulate vagal nereve,this will lead to Bradycardia ). *chronic effects :

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1. Tolerance : Tolerance and physical dependence are manifestations of chronic toxicity .

What does we mean by toleranc :Chronic(long) use there will be a reduction in drug efficiency (+pharmacodynamic in nature in which there is adaptation of central nervous system of usual doses of morphine).. **Tolerance develops To: 1)Analgesia 2)Euphoria 3) Sedation **While the Tolerance DOES NOT develop to: 1) Miosis 2)Constipation **Cross tolerance develops to other opioids ,for examples : For ex: Patient used morphine to control pain due to cancer, continuous used will lead to tolerance, if this patient switch to other opioids, the similar drug also become not effective because this drug is cross tolerance to other opioids. The most other problem with chronic use is dependence : 2. Dependence : characterized by physiological dependence and psychological dependence. Physical or physiological, sudden Abnormal physical state in which the drug must be administered to maintain normal function.

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Psychological dependence is addiction, while physical dependence is seen in which continuous drug used become essential to overcome withdrawal symptoms,in which this symptoms are highle severe. Physical dependence is a powerful reinforcement for continued drug taking behavior. They found thay withdrawal symptomscan be more severe if the patient use an antagonist. Withdrawal syndrome can be induced by naloxone(antagonist). withdrawal symptomsare highly severe if the patient suddenly stop the drug. Methadone:Produces very mild withdrawal or abstinence syndrome.

If we have an addict we need to treat this addict, how he/she can be treated ? for ex: individual who become addict to heroin, how we can treat this addiction ? Sudden withdrawal induce severe sudden abrupt discontinuation will induce severe withdrawal syndrome . we cant make gradual reduce in heroin,we use another drug which known as methadone ,this drug is used in program for the treatment of opiods addiction,in which methadone can produce euphorietic effect is less than that euphoria produce by heroin or morphine,the patient will get the euphorietic effect, which is lesser , and with time we can reduce methadone dose.This mean there is addicted,if this
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addicted receive the antagonist ,the antagonist will initially give excessive pain withdrawal symptoms , because the antagonist make longer symptoms,by that is like making sudden withdrawal drug,this will lead excessive withdrawal symptoms , the patient is switch to methadone and with time we reduce the dose of methadone, in which methadone is used orally for reduce euphoria , but is less than that of morphine and heroin and othersby that you will see methadone will reduce a mild withdrawal symptoms comparing with heroin. Therapeutic uses of morphine 1)Analgesic postoperative pain Cancer pain. Renal colic Therapeutic uses in the treatment of pain as an analgesia,chronic pain due to cancer ,pain of renal colic and to control postoperative pain. 2)for the treatment of Acute pulmonary edema due to left ventricular failure(LVF). To decrease anxiety and because of the vasodilation it will reduce the pre load and the after loads. 3)Antitussive in severe and refractory cough. codeine has greater antitussive effect than morphine. Morphine can be used as antitussive, it is effector,this is theory but in practical NO,because of the high risk of addiction.

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It is impossible to find morphine in antitussive cooperation , it is impossible because the high risk of dependence ,we can use other opiods derivatives With loss or no CNS addiction like dextramethrophan or As effect. 4)Preanesthetic medication: When we talk about anesthetia we talk about group of drug taken before administration anesthetic known as Preanesthetic medication. Each drug has specific aim : opidis can be used as Preanesthetic medication,to control postoperative pain, to sedate the pain , to relieve anxiety . 5)In the treatment of diarrhea , morphine is effective,but it seen it is impossible to find morphine tablets for control diarrhea,or morphine can be used voluntary morphine for diarrhea because of high risk of addiction, we will talk later on about another drug. ,has powerful antitussive effect with low or no addiction

Contraindications
Contraindications and cautions in therapy of morphine : 1)Bronchial asthma : and chronic respiratory diseases. Due to : Respiratory center depression , bronchoconstriction and histamine release. 2)In patient with acute head injury : because it increase ICP by that increase the risk of hemorrhage 3)Urinary retention: like-benign prostatic hyperplasia
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4)During pregnancy : they found to control labor pain in part, they found that morphine can penetrate placenta and induce respiratory depression in babies and withdrawal syndrome. 5)Impaired renal and hepatic functions, it is important because you know in liver as well as the kidney has a role in drug irritation. 6)Use of pure agonists with weak partial agonists. Vomising of pure agonist with drug that has a weak or partial agonist effect, drug that has mix agonist antagonist. Pure agonist it is used with the drug that has partial agonist effect or mixed agonist antagonist . Pure antagonist is used with drug that has partial agonist or mixed agonist antagonist . Now if mixed agonist antagonist used the a it will act >>> as an agonist >>>good for pain relieving. But if this drug used in combination with full agonist , like morphine, this drug will act >>> as an antagonist. The mixed agonist antagonist if it used with strong agonist it act as >>>antagonist ,this is mean it block the opioids receptor , by that is it ineffective control pain , ineffective in preanesthetic medication or Other opioids * Meperidine :(the other name is Pethidine). it is strong agonist
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less potent than morphine in high doses produce CNS excitation(because of its metabolites)and convulsions they found that Meperidine produce less smooth muscle spasm and less miosis, respiratory depressant effects. less antitussive effect comparint with morphine . because of that Meperidine is effective for relieving biliary colic , because of less miosis , in opising to other opioids lead to meperidine to produce mydriasis (not miosis), because of less muscle spasm, it is effective to control pain, it it the best opioids to control biliary colic uses : 1)Analgesic as substitute of Morphine 2)Preanaesthetic medication 3)As analgesic during labor (during labor we need a powerful analgesic, because it is a painful) ,less fetal respiratory depression. So the best selective opioids during labor is : Meperidine or pethidine ,it is the same name, because it has Heroin Has no medical used(not used clinically), commonly used between adults , highly addictive, because of high Methadone It is strong agonist.
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Oral less addictive than morphine, with no or mild withdrawal syndrome. Therapeutic uses: Used in the treatment of addiction. Methadone is used as an analgesic as well as in the controlled withdrawal of dependent abusers from heroin and morphine.

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