ANALGESICS drugs to treat pain

ANALGESICS drugs to treat pain

Pain and nociception Pain Nociception Nociceptors
an unpleasant subjective sensory and emotional experience associated with actual or potential tissue damage Nociception perception of noxious stimuli (Lat. Nocere – to injure) Nociceptors respond to noxious stimuli (higher treshold than e.g., mechanoreceptors) Stimulation of nociceptors nox. stimuli induce release of active substances (H+, K+, ATP, bradykinin, prostaglandines, histamine, leukotrienes, 5-HT, substance P, CGRP, NGF) Stimulus senzitize and/or activate nociceptors and AP is induced.

Nociception – transmission to CNS
Nociceptors = nerve endings of afferent neurons that have their cell bodies outside the spinal column in the dorsal root ganglion. Polymodal nociceptors C - nerve fibers thinner, non-myelinated, slower conduction, dull/burning non-localised pain High-threshold mechanoreceptors Aδ -n. fibers thicker, myelinated, rapid conduction, sharp/pricking localised pain Afferent nociceptive n. fibres enter the spinal corn via dorsal roots - dorsal horn There they synapse in various layers (laminae, above all - I, II, V) Neurotransmitters: glutamate, substance P, CGRP

Nociception – transmission to CNS

Spinocerebral transmission
Spinocerebral Ascending Pathways Interconnection on ascendant spinal cord pathways 2nd neurons - to the higher CNS centers - particularly thalamus spinothalamic and spinoreticular pathway are the major ones Pain perception takes place in the higher cortical structures projection through 3rd neuron To gyrus postcentralis perceive location, quality and intensity, allows to „feel“ pain, determine the emotional and other responses.

Gate theory THALAMUS Nociceptive afferents (C/Ad)
Gate control system Transmission neuron Descending Inhibitory pathways Nociceptive afferents (C/Ad) SG Mechanoreceptors (Ab)

Modulation of nociceptive stimuli
Gate-control theory (1995) lamina II - substantia gelatinosa - short inhibitory interneurons projecting to laminas I and V they inhibit transmission from primary afferent fibers on spinocerebral pathways. Their activity is modulated by nociceptive (C-fibers) as well as some non-nociceptive (A- fibers) neurons. Descending inhibitory controls Periaqueductal grey matter (PAG) neurons project to the rostral ventral medulla - Nucleus raphe magnus from which 5-HT neurons and enkephalin neurons project to the dorsal horn where directly or via interneurons inhibits discharge of spinothalamic (II.) neurons. Locus coeruleus another descendent inhibitory pathway from which NA neurons also project to the dorsal horn.

ANALGESIC DRUGS NARCOTIC ANALGESICS ANALGESIC-ANTIPYRETICS
morphine - like drugs – opioid ANALGESIC-ANTIPYRETICS Paracetamol + NSAID Other ways of pain suppresion causal therapy – vasodillators in IHD etc. general and local anesthetics, antiepileptics, capsaicin, ziconotide, cannabinoids

Opium, opiates, opioids Opium Opiates Opioids
dry juice of the poppy Papaver somniferum contains number of compounds including alkaloids: morphine, codeine and papaverine (Tinctura opii - laudanum) Opiates drugs derived from opium and number of their semisynthetic derivatives. Opioids any substance, that produces the morphine-like effects endogenous (enkefalines and dynorphines) or synthetic blocked with an antagonist like naloxone

Classification - structure
Morphine analogues (phenanthrenes): agonists (morphine, heroin, codeine) partial agonist (nalorphine, buprenorphine) antagonists (naloxone, naltrexone) Synthetic derivatives (structure unrelated to morphine): phenylpiperidine series, e.g. pethidine and fentanyl phenyheptylamines - e.g. methadone and dextropropoxyphene benzomorphan series, e.g. pentazocine morphinans - levorphanol semisynthetic thebaine derivatives, e.g. Buprenorphine Oripaviny - buprenorfin Morfinany – nalbufin Difenylpropylaminy - piritramid

Opioids

Mechanism of action - opioid receptors
GPCR - G proteins coupled inhibition of adenylyl cyclase – decreased cAMP associated with ion channels to increase K efflux (hyperpolarisation) reduce Ca influx (impeding neuronal firing and transmitter release). on the of certain cells mostly in the CNS and the GIT Three families m /mu/ - MOR (mu opioid receptors) analgesic activity, euphoria, sedation, respiratory depression, dependence, pupil constriction, constipation d /delta/ analgesia (spinal), constipation, resp. depression k /kappa/ analgesia at the spinal level, dysforia, sedation mu1-3, kappa 1-3 – developed by splicing variants of one gene!

Opioid receptor - function
m d k Analgesia Supraspinal Spinal Peripheral +++ ++ - + Respiratory depression Pupil constriction Reduced gastrointestinal motility Euphoria Dysphoria Sedation Physical dependence

Distribution of opioid receptors
Brainstem Receptors modulate respiration, cough, nausea and vomiting, pupillary diameter, descending pain inhibiting pathways – PAG, NRM. Medial thalamus modulate deep pain that is poorly localized and emotionally influenced. Spinal cord the attenuation of painful afferent stimuli. Hypothalamus affect neuroendocrine secretion Limbic system amygdala - influence on emotional behaviour. Periphery binding to peripheral sensory nerve fibers and terminals inhibition of the Ca-dependent release of pro-inflammatory substances /Substance P/ from endings) contribution to anti-inflammatory effects of opioids?

OPIOID ANALGESICS AND ANTAGONISTS
STRONG AGONISTS Alfentanil Fentanyl Heroin Pethidine Methadone Morphine Remifentanil Sufentanil MODERATE/LOW AGONISTS Codeine Oxycodone Propoxyphene MIXED AGONIST-ANTAGONISTS AND PARTIAL AGONISTS Buprenorphine Butophanol Nalbuphine Pentazocine ANTAGONISTS Naloxone Naltrexone OTHER ANALGESICS Tramadol

Classification - in relation to the activity
Strong agonists morphine, meperidine=pethidine, methadone, fentanyl, sufentanil, alfentanil, remifentanil Moderate agonists e.g. propoxyphene, codein, oxycodone Mixed agonist-antagonists pentazocine, buprenorphine, nalbuphine, butorphanol Other analgesics Tramadol, Tapentanol Antagonists naloxone, naltrexone

Mixed agonist-antagonists pentazocine nalbuphine nalorphine A- P++
k d Full agonists morphine pethidine methadone fentanyl sufentanil codein +++ ++ ++++ + Partial agonists buprenorfin P+++ A-- Mixed agonist-antagonists pentazocine nalbuphine nalorphine A- P++ Antagonists naloxone naltrexone A--- Endogenous opioids b-endorphin leu-enkephalin met-enkephalin dynorfin Atypické opioidy – tramadol nízká afinita k m-receptorům + neopiodní mechanismy = blokáda zpětného vychytávání noradrenalinu a serotoninu do nervových zakončení

Opioid pharmacokinetics – mainly lipophilic
Administration/absorption morphine erratic absorption from the GIT – BAV – 10-50% Significant first-pass metabolism of morphine occurs in the liver given i.m., s. c. or i.v. injections produce the most reliable responses controlled-release preparations for oral administrations chronic pain in cancer etc. Codeine, methadone - well absorbed when given by mouth Fentanyl, buprenorphine – very low oral bioavailability Distribution: opioids rapidly enters all body tissues, including the fetuses, often used during obstetric labor – caution, naloxone if respir depression Only a small percentage of morphine crosses the blood-brain barrier because morphine is the least lipophilic of the common opioids This contrasts with the more lipophilic opioids such as fentanyl and heroin, which readily penetrate into the brain

Morphine pharmacokinetics
Elimination Morphine is conjugated in the liver - Morphine-6-glucuronide ACTIVE and very potent analgesic, conjugate at the 3-position is much less active. The conjugates are excreted primarily in the urine – Caution renal failure CYP3A4 – pethidine, fentanyl, alfentanyl CYP2D6 – codeine – active metabolite, tramadol – active metabolite oxycodone, hydrocodone – metabolites less important for effect Morphine - the duration of action is 4 – 6 hours when administered systemically longer when injected epidurally, its low lipophilicity prevents redistribution from the epidural space. Elderly patients are more sensitive to morphine possibly due to decreased metabolism or other factors, such as decreased lean body mass, renal function, etc. lower doses Neonates should not receive morphine low conjugating capacity + BBB immaturity (Katzung). KOI: při poškozené funkci plic s útlumem dýchacího centra, chronické obstrukční chorobě bronchopulmonální, při paralytickém ileu a úrazech hlavy se zvýšeným intrakraniálním tlakem

PK morphine Dose? Morphine (circles, A), morphine-3-glucuronide (triangles, B), and morphine-6-glucuronide (squares, B) serum concentration vs. time profiles in healthy subjects (gray) and patients with NASH (black). Data are presented as geometric mean and 95% confidence intervals (CIs). Ferslew BC et al. CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 97 NUMBER 4 | APRIL 2015

Opioids – CNS effects Analgesia Sedation Euphoria
relief of pain without the loss of consciousness sensory and emotional/affective components, alteration of brain´s interpretation of pain Patients are still aware of the presence of pain, but the sensation is not unpleasant. relief of anxiety Sedation commonly drowsiness after administration little or no amnesia more with phenathrenes – less with pethidin Euphoria powerful sense of satisfaction and well-being euphoria typically after intravenous administration euphoria may be caused by stimulation of the ventral tegmentum

Opioids – CNS effects Respiratory depression:
reduces the sensitivity of respiratory center to carbon dioxide Dose-dependent This occurs with ordinary doses of morphine High doses - respiration ceases the most common cause of death in acute opioid overdose Depression of cough reflex The cough suppression does not correlate with analgesic and respiratory depressant effect The receptors involved in the antitussive action appear to be different than those involved in analgesia. codeine < ethylmorphine < pholcodine Nausea and vomiting direct stimulation of the chemoreceptor trigger zone in the area postrema. emesis does not produce unpleasant sensations.

Opioids – CNS effects Miosis
the pinpoint pupil characteristic of morphine use results from stimulation of m and k receptors. Excitation of the Edinger-Westphal nucleus of the oculomotor nerve enhanced parasympathetic stimulation to the eye. Little tolerance to the effect all addicts - pin-point pupils except pethidine important diagnostically most other causes of coma and respiratory depression produce dilation of the pupil !

Opioids – CNS effects Truncal rigidity increased tonus of muscles
more significant with more potent – fentanyl etc Increased disposition to convulsions Increased polysynaptic spinal cord activity Straub tail reaction in mice raising and stiffening of the tail due to the spasm of a muscle at the base of the tail.

Opioids – GIT effects Morphine produces constipation
It decreases motility (propulsive peristaltic waves) and increases tone of smooth muscle! spasms of shincters !! with little tolerance developing It relieves diarrhea and dysentery Morphine increases pressure in the biliary tract !! harmful in biliary colic due to gallstones!! Morphine can cause urethral spasms retention of urine catheterization in intoxication with M.

Opioids – cardiovascular effects
in healthy person no major effects on the blood pressure or heart rate in cardiovascular system in stress or high doses bradycardia - hypotension arterial and venous vasodilation Due histamine release + vasomotor center depression vasodilation of cerebral vessels and increase the cerebrospinal fluid pressure due to the carbon dioxide retention Morphine usually contraindicated in severe brain injury

Opioids – other effects
Histamine release morphine from mast cells displacement not degranulation! Pulmonary oedema bronchoconstriction, urticaria, itching, sweating, hypotension Asthmatics should not receive the drug. Hormonal actions inhibition of the release of GRH and CRH gonadotropin-releasing h. and corticotropin-releasing h. LH, testosterone and cortisol levels decrease. man – decreased libido, energy, mood; women dysmenorrhea or amonorrhea increases secretion of antidiuretic hormone urinary retention Note: It also can inhibit the urinary bladder voiding reflex catheterization may be required. Pruritus - - histamin release + pruritoceptive neural circuits; upon spinal or epidural administratin - pruritus over lips and torso – % patients Immunosupresive effect by inhibition of proliferation of NK and Lymphocytes, and leucote migration

Clinical use of opioids
Analgesia only few other drugs are as effective as Morphine severe constant pain is usually relieved whereas sharp, intermittent pain does not appear to be as effectivel controlled cancer pain long term treatment – sustained /controlled release forms oral, buccal (lozenge or lollipops), transdermal obstetric labor opioid cross placental barrier pethidine less respiratory depression – preffered Anesthesia can also induce somnolence/sleep/anxiolytic clinical situations when pain is present and sleep is necessary. premedication or during surgery epidural administration after major surgeries

Clinical use of opioids
Treatment of diarrhea decrease the motility of smooth muscle and increase tone of sphincters Tinctura opii , dyfenoxylate CNS action - dependence diphenoxylate, loperamide non-CNS acting Suppression of cough irritating dry cough which exhausts patients codeine or dextromethorphan are more widely used. Acute pulmonary edema I.V. morphine relieves dyspnea caused by pulmonary edema associated with left ventricular failure vasodilatory effect (reduced preload and afterload) + decrease breathing frequency (decreases 02 consumption) + reduced anxiety the opioids may prolong labor by relaxing the uterine contractility pethidine block most potently shivering by action on alpha2 receptors

Adverse effects Overdose Constipation, vomiting, dysphoria, sedation
Severe respiratory depression occurs, hypotension, coma and death! Constipation, vomiting, dysphoria, sedation Pseudo - Allergy enhanced bronchoconstriction, hypotensive effects, itching - dyspnea in emphysema or cor pulmonale patients. The elevation of intracranial pressure, particularly in head injury, can be serious. It enhances cerebral and spinal ischemia. Urinary retention (particularly in high doses/in prostatic hypertrophy). Drug dependence! Use with caution in patients with bronchial asthma or liver failure. při poškozené funkci plic s útlumem dýchacího centra, chronické obstrukční chorobě bronchopulmonální, při paralytickém ileu a úrazech hlavy se zvýšeným intrakraniálním tlakem

Adverse effects commonly observed in individuals treated with opioids.
(according to Lippincott´s Pharmacology, 2006

Tolerance and dependence
Tolerance also develops on therapeutic dosage by increased cAMP synthesis and increased MOR receptor endocytosis upregulation of receptors for glutamate - NMDA including hyperalgesia but not to the pupil-constricting and constipating effects high degree - develop to therapeutic and toxic effects 60 mg first dose of morphine may cause respiratory depression addicted person may tolerate 2 g! crosstolerance not complete between different structures – „opioid rotation“ Dependence and addiction readily occur with morphine and with some of the other agonists. Withdrawal produces a series of autonomic, motor, and psychological responses cause serious-almost unbearable-symptoms However, it is very rare that the effects are so profound as to cause death. high potent agents applied with higher doses – more rapid development of tolerance even within day – otherwise start to develop over 2-3 weeks high degree

Withdrawal syndrome Onset Severity Early symptoms Later symptoms
given by t1/2, h for heroin Severity Given by dosage schedule and duration Early symptoms resembling severe influenza, fever with yawning, piloerection, sweating Later symptoms pupillary dilatation, then nausea, diarrhea and insomnia. Extreme restlessness and distress strong craving for the drug The physical symptoms are maximal after 1-2 days and largely disappear in 8-10 days, some residual symptoms and physiological abnormalities persist for several weeks. Re-administration of morphine (codein) rapidly abolishes the abstinence syndrome buprenorphine (prefered in CZ), methadone, or clonidine are FDA approved for opioid analgesic detoxication

Contraindications/care of opioids
Impaired respiratory functions/Respiratory center depression COBPD Paralytic ileus Head injuries/ increased intracranial pressure CO2 – increased intracranial pressure Caution Colics, prostatic hypertrophy Asthma Pregnancy, breastfeding, age bellow 1/2 pethidin preffered Hepatic or renal failure dose correction Age bellow 1 year

Drugs interacting with narcotic analgesics.
CNS = central nervous system; MAO = monoamine oxidase Narcotic analgesics Absolute contraindication to meperidine and relative contraindication to other marcotic analgesics because of high incidence of hyperpyretic coma Increased CNS depression, particularly respiratory depression Sedative- hypnotics MAO inhibitors Narcotic analgesics Tricyclic anti-depressants Antipsychotic drugs (according to Lippincott´s Pharmacology, 2006 Increased sedation; variable effects on respiratory depression

Time to peak effect and duration of action of several opioids administered intravenously.
Key Duration of action 20 minutes Morphine 4 hours 15 minutes Pethidine 2 – 4 hours 5 minutes Fentanyl 15 – 30 minutes (according to Lippincott´s Pharmacology, 2006

PETHIDINE (meperidine)
shorter duration of the action 2-4 h not biotransformed by conjugation which is deficient in newborns - preferred during childbearing N-demethylated in the liver to norpethidine rather restlessness than sedation AE: anxiety, tremor, muscle twiches hallucinogenic and convulsant effects - after large oral dose antimuscarinic - atropine-like action - AE no miosis! less spasms of smooth muscle, dry mouth, blurring of vision less urinary retention, but AE tachycardia!! less frequently used 80 tis DDD v roce 2012 – spotřeba ustupuje kvůli nežádoucím účinkům – morfin 1 mil DDD, hydromorfon 601 tis DDD, fentanyl 2,7 mil DDD, pyritramid 220 tis DDD, pentazocin 121 tis DDD, buprenorfin 1,1 mil DDD, pentazocin – 120 tis. DDD; codein 720 tis DDD, oxycodon 1,2 mil DDD, DHC 2,4 mil DDD, tramadol 16 mil DDD + 5 mil v kombinacich; tapentanol jen 23 tis DDD; paracetamol 37 mil DDD, ASA 6 mil DDD lower antitussive effect Severe hypotension - can occur when the drug is administered postoperatively Drug dependence partial cross-tolerance with the other opioids occurs.

Piritramide Afinitou i aktivitou podobný morfinu Nepůsobí sedaci
Podáván parenterálně Působí 6 h Nepůsobí sedaci Bez vlivu na kardiovaskulární systém Ne hypotenze nebo bradykardie

METHADONE Synthetic, orally effective opioid induces less euphoria
readily absorbed induces less euphoria has a longer duration of action The analgesic activity is equivalent to morphine It also increases biliary pressure and is also constipating. Therapeutic uses substitution in abusers causes a withdrawal syndrome that is milder but more protracted (days to weeks) than with other opioids long t1/2 due to slow release from tissues where accumulate Cross-tolerance with heroin prevents its effect !! more overdose fatalities – addict try to override by increased heroin dose

FENTANYL 100-fold the analgesic potency of morphine
rapid onset and short duration of action minutes, injected i.v., epidurally, or intrathecally Special formulation (drug delivery systems) transmucosal preparation transdermal patches with controlled continuous drug delivery up to 12h Transdermal patch must be used with caution, death resulting from hypoventilation has been known to occur. It is metabolized to inactive metabolites by the cytochrome P4503A4 drugs that inhibit this isozyme can potentiate the effect of fentanyl. It is also used in neuroleptanalgesia (with droperidol) Alfentanyl, sufentanyl, remifentanil sufentanyl more potent than fentanyl, while alfentanyl less but short acting remifentanyl extremely potent but excessively degraded by esterases – other phenylpiperidines by CYP450

Heroin (diamorphine) It is synthetic compound,
di-acetylated derivative of morphine, Its greater lipid solubility allows it to cross the blood-brain barrier more rapidly than morphine which leads to a threefold increase in its potency. a more exaggerated euphoria when taken by injection gives greater "rush", shorter duration of action (2 hrs) very strong dependence It has no accepted medical use – drug of abuse

MODERATE AGONISTS - CODEINE (methylmorphine)
much less potent analgesic than morphine about 20% of the analgesic potency of morphine mild types of pain. higher oral effectiveness more lipophilic better absorption after p.o. administration good antitussive activity at doses that do not cause analgesia dextromethorphan has a lower potential for abuse, dependence lower euphoria than morphine. Frequently combined in analgesic-antipyretic preparations with salicylates or paracetamol. Adverse effects - constipation

DEPRESSES COUGH REFLEX
Some actions of codeine ANALGESIA SEDATION EUPHORIA DEPRESSES COUGH REFLEX (according to Lippincott´s Pharmacology, 2006)

OXYCODONE, DHC PROPOXYPHENE
A semisynthetic derivative of morphine. It is orally active and is sometimes formulated with aspirin or paracetamol. activity as codein prescribed in higher doses for moderate so severe pain commonly SR/CR formulations The „dextro“ isomer is used as an analgesic A weaker analgesic action than codeine Often used in combination with aspirin or paracetamol. When used with alcohol and sedatives → a severe CNS depression, death by respiratory depression and cardiotoxicity can results – withdrawn/ex propoxyphene – není registrován v ČR

MIXED AGONIST-ANTAGONISTS AND PARTIAL AGONISTS
partial agonis at mu receptor and agonist at kappa receptor partial agonists In individuals who have not recently received opioids, mixed agonist-antagonists show agonist activity and are used to relieve pain. In the patient with opioid dependence, the agonist-antagonist drugs may show primarily blocking effects-that is, provokes withdrawal symptoms.

Selectivity of opioid drugs and peptides for receptor subtypes
m d k Opioids Partial mixed agonists Pentazocine, butorphanol Nalbuphine - + (++) Nalorphine (++) Buprenorphine (+++) Antagonists Naloxone Naltrexone represent agonist activity, partial agonists in parentheses - denote antagonist activity 0 represent weak or no activity

PENTAZOCINE an agonist on k receptors, used to relieve moderate pain
a weak antagonist at m and d receptors. used to relieve moderate pain analgesia by activating receptors in the spinal cord less euphoria compared to morphine orally or parenterally ADVERSE REACTIONS dysphoria! higher doses can cause hallucinations, nightmares, tachycardia reduced BP, and dizziness. it does not antagonize the respiratory depression of morphine, but it can precipitate a withdrawal syndrome in a morphine abuser. Tolerance and dependence develop on repeated use.

NALBUPHINE and BUTORPHANOL
only a limited role in the treatment of chronic pain - neither is available for oral use. Their propensity to cause psychotomimetic effects is less than that of pentazocine. Nalbuphine does not affect the heart or increase blood pressure, in contrast to pentazocine and butorphanol. A benefit of all three medications is that they exhibit a ceiling effect for respiratory depression.

BUPRENORPHINE a partial agonist longer duration of action
acting at the m receptor it can also precipitate withdrawal in morphine users. longer duration of action slow dissociation from receptors sublingually/buccally or transdermal patch low BAV Ind: cancer pain not responding to NSAID not suitable for acute pain – long duration Ind: opiate detoxication + naloxon because it has a less severe and shorter duration of withdrawal symptoms Adverse effects: respiratory depression, nausea, dizziness, dysphoria. 80 tis DDD v roce 2012 – spotřeba ustupuje kvůli nežádoucím účinkům – morfin 1 mil DDD, hydromorfon 601 tis DDD, fentanyl 2,7 mil DDD, pyritramid 220 tis DDD, pentazocin 121 tis DDD, buprenorfin 1,1 mil DDD, pentazocin – 120 tis. DDD; codein 720 tis DDD, oxycodon 1,2 mil DDD, DHC 2,4 mil DDD, tramadol 16 mil DDD + 5 mil v kombinacich; tapentanol jen 23 tis DDD; paracetamol 37 mil DDD, ASA 6 mil DDD respiratory depression that cannot be fully reversed by naloxone,

TRAMADOL Racemic mixture of both R- and S-stereoisomers
Bioactivated by CYP2D6 binds to the m opioid receptor. inhibits re-uptake of noradrenaline and serotonin. naloxone can only partially reverse its action The drug undergoes extensive metabolism, CYP2D6 – racemate – R-Desmethyl Used in moderate to moderately severe pain. AE: very low respiratory-depressant activity may predispose to seisures – relative COI during epilepsy nause, dizziness Tramadol should be avoided in patients taking MAO-I and SSRI !!!! serotonin syndrome precipitation Tapentanol new derivative – low use in CR

Competitive antagonists
They bind with high affinity to opioid receptors, but fail to activate the receptor-mediated response no intrinsic activity produce no effects in normal individuals in patients dependent on opioids they rapidly reverse the effect of agonists and precipitate the symptoms of opiate withdrawal

NALOXONE i.v. - used to reverse the coma and respiratory depression of opioid overdose. sublingually with buprenorphine – therapy of addiction per os with oxycodone – reduction of constipation competitive antagonist at m, k and d, receptors, with a ten-fold higher affinity for m receptors than for k reverses respiratory depression with only minimal reversal of the analgesia that results from agonist stimulation of k receptors in the spinal cord The effect within 30 seconds of i.v naloxone causing the patient to be revived and alert. A half-life of 60 to 100 minutes short duration of action, after recovered it may lapse back into respiratory depression. Pyritramid – U kojenců a dětí mezi 2 měsíci a 4 roky je terminální eliminační poločas přibližně 2,7 hodiny. Subutrex – cisty buprenorfin subuxon - buprenorfin+ naloxon

NALTREXONE longer duration of action than naloxone,
single oral dose of naltrexone blocks the effect of injected heroin for up to 48 hours. Ind: chronic alcoholism reduced dopamin release - decreased reward? Adverse effect: hepatotoxicity (NALORPHINE - partial agonist of morphine, used previously as an antidote in acute morphine and heroine overdosage; it can not antagonize effects of pentazocine and other partial agonists, none or few clinical use) but benzodiazopines and clonidine are preferred.

Analgesics - antipyretics Nonsteroidal antiinflamatory dugs (NSAIDs)

INFLAMMATION a normal, protective response to tissue injury
to inactivate or destroy invading organisms or irritants to set the stage for tissue repair should subsides, when healing is complete sometimes it is inappropriately triggered by otherwise innocuous stimuli pollen, an autoimmune response then the defense reactions themselves may cause progressive tissue injury anti-inflammatory or immuno-suppressive drugs may be required to modulate the inflammatory process. triggered by the release amines - histamine and 5-HT prostaglandins, small peptides (bradykinin), larger peptides, INF-kB-TNFa/L-1b dolor, calor, rubor and tumor

PROSTAGLANDINS Act as a local mediators
they are produced in minute quantities by virtually all tissues on the tissues in which they are synthesized rapid local metabolism they do not circulate in the blood in significant concentrations. Thromboxanes, leukotrienes, and prostaglandins are related compounds sometimes referred to as „eicosanoids“ "eicosa" refers to the twenty carbon atoms. Influenced by all nonsteroidal anti-inflammatory drugs (NSAIDs) inhibition of prostaglandins synthesis

Prostaglandins Arachidonic acid Phospholipase A2 Two major pathways:
the primary precursor of the PGS and related compounds present as a component of the phospholipids of cell membranes. Phospholipase A2 enzymes releasing arachidonic acids from membranes Two major pathways: Cyclooxygenase pathway COX-1/COX-2): → PGS, thromboxanes, prostacyclins. Lipoxygenase leucotriens Eicosanoids – 20 C molecule

AA – COX pathway

Cyclooxygenase COX-1 - constitutive isoform
that regulates normal cellular processes e.g. gastric cytoprotection, platelet aggregation, and renal perfusion COX-2 - „inducible“ isoform, increased during states of inflammation The two enzymes share > 60% homology in amino acid sequence. the substrate binding sites and catalytic regions are different e.g., COX-2 has a large space „ side pocket“ at the site where inhibitors bind development of COX-2-selective inhibitors. COX-2 expression is also inhibited by glucocorticoids they also inhibit fosfolipase A contribute to the significant anti-inflammatory effects of these drugs

(bronchoconstrictor; (bronchoconstrictors;
Summary diagram of the inflammatory mediators derived from phospholipids with an outline of their actions, and the sites of action of anti-inflammatory drugs. (according to Rang and Dale, Pharmacology, 2007) Phospholipid Glucocorticoids (induce lipocortin) Phospholipase A2 Arachidonate Lyso-glyceryl- phosphorylcholine 12-Lipoxygenase Cyclo-oxygenase 5-Lipoxygenase PAF antagonists NSAIDs 15-Lipoxygenase Cyclic endoperoxides 5-HPETE Glucocorticoids inhibit induction TXA2 synthase inhibitors 5-Lipoxygenase inhibitors (e.g. zileutin) PAF (vasodilator; increases vascular permeability; bronchoconstrictor; chemotaxin) TXA2 (thrombotic; vasoconstrictor) 12-HETE (chemotaxin) Lipoxins A and B PGI2 (vasodilator; hyperalgesics; stops platelet aggregation) TXA2 antagonists LTA4 Leukotriene receptor antagonists, e.g. zafirukast, montelukast LTB4 (chemotaxin) PG antagonists PGF2a (bronchoconstrictor; myometrial contraction) PGD2 (inhibits platelet aggregation; vasodilator) PGE2 (vasodilator; hyperalgesic) LTC4 (bronchoconstrictors; increase vascular permeability) LTD4 LTE4

Effects of PGS Most mediated by binding to GPCRs
G-protein-coupled coupled with adenylyl cyclase or stimulate phospholipase C → DAG and IP3. PGF2a, leukotrienes and thromboxane A2 stimulate phosphatidylinositol metabolism and causing an increase of intracellular Ca2+.

PG - Functions in the body
act as local signals produced in tissues functions vary widely depending on the tissue e.g., the release of TXA2 from platelets triggers the recruitment of new platelets for aggregation (the first step in clot formation). However, in other tissues, elevated levels of TXA2 convey a different signal; e.g., smooth muscle contraction. allergic and inflammatory processes PGS are also among the mediators released

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS - NSAID
chemically dissimilar agents antipyretic, analgesic, and anti-inflammatory activities they differ in relative potency act by inhibiting the COX enzymes COX-2 – nonselective – preferential - selective decreased PGS synthesis Antipyretic effect lowering a raised, not normal temperature due to a decrease in PGE2 production in hypothalamus, PGE2 is generated when an endogenous fever-producing agent (pyrogen), such as a cytokine (IL-1), is released from white cells that are activated by infection, hypersensitivity, malignancy, or inflammation.

NSAIDs Analgesic Anti-inflammatory Antiplatelet
by decreasing PGE2 synthesis, NSAIDs repress the sensation of pain. PGE2 is thought to sensitize nociceptors to the action of bradykinin, histamine, and other mediators released by the inflammatory process decreased PGs-mediated vasodilatation contributes to relief of eg headache Anti-inflammatory decrease in PGE2 and PGI2 - less vasodilatation, less oedema…. inhibition of chemotaxis, reduction of IL-1 production Antiplatelet ASA-irreversible – other reversible COX-2 selective – do not affect

A comparison of cyclooxygenase (COX) isozyme selectivity of
non-steroidal anti-inflammatory drugs (NSAIDs) -3 Rofecoxib -2 Etodolac Celecoxib Meloxicam Meclofenamate Nimesulide Diclofenac -1 Sodium salicylate Tomoxiprol Sulindac Piroxicam Niflumic acid Zomepirac Diflunisal log (IC80 ratio COX-2/COX1) Fenoprofen 1 Tolmetin Aspirin Ibuprofen Ampyrone Naproxen Ketoprofen Indometacin 2 Suprofen Flurbiprofen 3 5-50-fold COX-2 selective Ketorolac COX-1 selective < 5-fold COX-2 selective > 5-fold COX-2 selective (according to Rang and Dale, Pharmacology, 2007)

NSAID - PK lipophilic different molecules – commonly weak acids
well absorbed, highly protein bind – albumin - interactions CYP450 metabolism active secretion in proximal tubuli - interactions all undergoes at least some enterohepatic circulation cross both the blood-brain barrier and the placenta not suitable in 3rd trimester; ASA not at all, only eclampsia Administration and distribution: - Salicylates, especially methyl salicylate, are absorbed through intact skin. - After oral administration, the unionized salicylates are passively absorbed from the stomach and the small intestine. - Salicylates (except for diflunisal) cross both the blood-brain barrier and the placenta.

Adverse effects of NSAID
GIT – abdominal pain, nausea/vomiting, ulcers PGI2 is protective inhibits gastric acid secretion, stimulate the production of bicarbonate. PGE2 and PGF2a stimulate synthesis of protective mucus in both the stomach and small intestine. also important for adequate microcirculation AE - dose and time related aspirin and other NSAIDs can cause the peptic ulcer development or its progression - perforation, bleeding Rules for oral administration effervescent forms could be better, fluides help, empty stomach- worse Hemostasis bleeding - occult, manifests – ulcers, GIT, epistaxis during surgery - aspirin should be withdrawn 10 day before surgery All differe in intensity

Hypersensitivity: About 15 % of patients - urticaria, bronchoconstriction, or angioneurotic edema Fatal anaphylactic shock is rare. Aspirin sensitive asthma in some patients aspirin exacerbate asthmata This appears to be of non-allergic origin! Inhibition of COX pathway induces Lipooxygenase pathway resulting into leucotrienes is preffered?!!! Kidney PGE2 and PGl2 are responsible for maintaining renal blood flow. Decreased synthesis of PGS - retention of sodium and water cause edema and hyperkalemia in some patients. Dose and time related PGI inhibits sodium reabsorption in proximal tubuli

Hepatotoxicity concentration of drug in the liver – any NSAID CNS headaches, tinnitus, dizzines Cardiovascular fluid retention, hypertension, edema rarely congestive heart failure Reye syndrome - ASA Rarely during ASA administration to children for viral infections often fatal, fulminating hepatitis with cerebral edema -hepatoencephalopathy ASA Contraindicated in children bellow 12 years od age paracetamol is preffered !!!

ASPIRIN and other salicylates
prototype is the drug to which all other anti-inflammatory agents are compared. About 15 % of patients show an intolerance newer NSAIDs Most are superior to aspirin in certain patients greater anti-inflammatory activity and/or less gastric irritation, some can be taken less frequently. more expensive some have proved to be more toxic in other ways.

Salicylates acetylsalicylic acid (ASA) Diflunisal sodium salicylate
not antiplatelet, anti-inflammatory methylsalicylate (topically used)

ASA irreversibly acetylate COX ASA rapidly metabolized to SA
antiplatelet action other NSAIDs - reversible inhibitors of COX ASA rapidly metabolized to SA in the liver during first pass SA - salicylate possess systemic anti-inflammatory, antipyretic, and analgesic effects of ASA Low dose ASA long-term administration decreases the incidence of TIA, unstable angina lowers incidence of colon cancer? Aspirin may also depress pain stimuli in the thalamus and hypothalamus TIA – transient ischemic attacks

ASA systemic plasma concentration
Log-linear plot curves of aspirin (ASA)(left figure) and salicylic acid (SA)(right figure) plasma concentrations after oral administration of 500 mg ASA and co-administration of 400 and 800 μg capsaicin tablets in 15 healthy male volunteers Capsaicin is a New Gastrointestinal Mucosal Protecting Drug Candidate in Humans — Pharmaceutical Development and Production Based on Clinical Pharmacology

Therapeutical effects of ASA
Antipyretic effects 500 mg - not to be used in children Analgesic effects 500 mg - treatment of pain of low to moderate intensity. high effect on iflammation related pain. Headache, arthralgia, and myalgia Low effects on visceral pain, Anti-inflammatory actions > 4 g/day - often poorly tolerable. Antiplatelet action mg, typically 100 mg/day irreversible inhibition TXA2 production in the platelets inhibits their aggregation as the 1st phase of arterial trombus formation - white trombus secondary prevention of CAD, stroke, leg ischemia Keratolytic – topical > 2% Other salicylates are used rarely or topically for inflammation

Aspirin overdose salicylism severe salicylate intoxication Children
milder form - nausea, vomiting, marked hyperventilation, headache, mental confusion, excitation, dizziness, and tinnitus (ringing or roaring in the ears). severe salicylate intoxication restlessness, delirium, hallucinations, convulsions, coma, respiratory and metabolic acidosis, and death from respiratory failure. Children are particularly prone to salicylate intoxication. Treatment of salicylism measurement of serum salicylate concentrations and blood pH to determine the best form of therapy. mild symptomatic treatment is usually sufficient - Increasing the urinary pH (its alkalisation) enhances the elimination of salicylate. serious i.v. administration of fluid, hemodialysis or peritoneal dialysis, compensation of acid-base and electrolyte balances. Note: Diflunisal does not cause salicylism.

Plasma concetration of
Dose-dependent effects of salicylate Vasomotor collapse; Coma; Dehydration Lethal Severe Mild 150 Intoxication 100 50 Plasma concetration of salicylate (mg/dL) Tinnitus Cental hyperventilation Anti-inflammatory 10 Analgesic Antipyretic Antiplatelet Gastric bleeding Impaired blood clotting Hypersensitivity reactions (according to Lippincott´s Pharmacology, 2006

Effect of dose on the half-life of aspirin
Aspirin Aspirin (low dose) (high dose) 12 3 2 1 12 12 11 1 11 1 10 2 10 2 9 3 9 3 8 4 8 4 7 5 7 5 6 t1/2 = 3 hours t1/2 = 15 hours (according to Lippincott´s Pharmacology, 2006

Decreased urate excretion (contraindicated patients with gout)
Drugs interacting with salicylates Decreased urate excretion (contraindicated patients with gout) Probenecid Sulfinpyrazone Hemorrhage Probenecid Sulfinpyrazone Heparin or oral anticoagulants Reduced rate of aspirin absorption Antacids SALICYLATES Bilirubin Phenytoin Naproxen Sulfinpyrazone Thiopental Thyroxine Triiodothyronine (according to Lippincott´s Pharmacology, 2006 Increased plasma concentration leading to prolonged half-lives, therapeutic effects, and toxicity

Propionic acid derivatives
IBUPROFEN Related drugs: ketoprofen, naproxen, dexketoprofen Anti-inflammatory, analgesic, antipyretic activity ibuprofen antiinflammatory since 2.4 g/day Well-tolerated GIT effects are generally less intense than that of ASA commonly in the chronic treatment of rheumatoid arthritis and osteoarthritis flurbiprofen more complex action – inhibits NO and TNFa production also i.v. for perioperative analgesia in minor surgeries AE: NSAID typical + rigidity, tremor, ataxia IBUPROFEN [eye BYOO proe fen] Related drugs: ketoprofen [key toe PROE fen], flurbiprofen [flur bye PROE fen], naproxen [nah PROX en]

Acetic acid derivatives
INDOMETHACIN mainly in the treatment of pain and inflammation administration – local (eye drops), systematic - rectal – suppositories, oral, not SR forms Despite its potency, the toxicity of indomethacin limits its use Ind: acute gouty arthritis, ankylosing spondylitis, and osteoarthritis Adverse effect: very common (up to 50%, for 20% is intolerable) GIT - nausea/vomiting, anorexia, diarrhea, abdominal pain, perforation; hepatoxicity, pancreatitis, CNS – headache, dizzines, vertigo, confusion, hematopoetic distubances, hypersenstivity ACEMETACIN metabolized to indometacine – better tolerance SULINDAC an inactive prodrug, closely related to indomethacin The adverse reactions are less severe than, those of the other NSAIDs, including indomethacin.

NAUSE AND VOMITING GI DIARRHEA ANOREXIA HEADACHE
Some adverse effects of indomethacin NAUSE AND VOMITING GI DISTURBANCES DIARRHEA ANOREXIA HEADACHE (according to Lippincott´s Pharmacology, 2000)

DICLOFENAC Excellent analgesic Accumulates in synovial fluid
It is more potent than indomethacin or naproxen Accumulates in synovial fluid Approved for long-term use in the treatment of rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. Administered locally (topically - gels) and systematically - orally, sustained release formulations avialable PK/AE typical to NSAIDs Its toxicity - similar or less to the other NSAIDs. GIT problems are common, elevation of hepatic enzymes. Aceclofenac - similar

Piroxicam Oxicam derivatives they have long half-lives → administration once a day RA, ankylosing spondylitis, and osteoarthritis. Piroxicam T1/2 – 45 hours GI disturbances in approximately 20 % of patients Meloxicam relatively COX-2 selective and at low to moderate doses shows less GI irritation than piroxicam. At high doses, is a nonselective NSAID, inhibiting both COX-1 and COX-2. Lornoxicam More selective, rapid absorption PIROXICAM [peer OX i kam] and MELOXICAM [mel OX i kam] MEFENAMIC ACID [meh FEN a mick] and MECLOFENAMATE [meh KLO fen a mate] have no advantages over other NSAIDs as anti-inflammatory agents. Side effects: e.g., diarrhea (even severe with inflammation of the bowel, hemolytic anemia). Piroxicam and its metabolites are excreted in the urine.

Pyrazolones Phenylbutason,: oxyphenbutazone, kebuzone, propyphenazone, aminophenazon Powerful anti-inflammatory effects, weak analgesic and antipyretic activities. limited by its toxicity – obsolent now. serious agranulocytosis and aplastic anemia, but it has number of other (GIT, CNS, skin rashes….) METAMIZOL powerful analgesic effect with some spasmolytic action minor antiflogistic effects rapidly and completely absorbed after oral or rectal administration Sole or contained in mixtures with other spasmolytics

COX-2 preferential drugs
NIMESULID, DIACEREIN, NABUMETONE potent and more selective antiinflammatory action (in treating rheumatoid arthritis or osteoarthritis), act preferentially selectivity to COX-2, lower adverse effects. Nimesulid hepatotoxicity??? Better to cartilageous – support formation Diacerein - ??? Mechanism – inhibits proinflammatory cytokines without influence on COX – no GIT AE

A comparison of cyclooxygenase (COX) isozyme selectivity of
non-steroidal anti-inflammatory drugs (NSAIDs) -3 Rofecoxib -2 Etodolac Celecoxib Meloxicam Meclofenamate Nimesulide Diclofenac -1 Sodium salicylate Tomoxiprol Sulindac Piroxicam Niflumic acid Zomepirac Diflunisal log (IC80 ratio COX-2/COX1) Fenoprofen 1 Tolmetin Aspirin Ibuprofen Ampyrone Naproxen Ketoprofen Indometacin 2 Suprofen Flurbiprofen 3 5-50-fold COX-2 selective Ketorolac COX-1 selective < 5-fold COX-2 selective > 5-fold COX-2 selective (according to Rang and Dale, Pharmacology, 2007)

COX-2-SELECTIVE NSAIDs
celecoxib, parekoxib, etoricoxib The structural difference between COX-1 and COX-2 allowed the development of COX-2-selective agents, such as no impact on platelet aggregation is COX-1 mediated lower risk of GI bleeding no cardioprotective effects of nonselective – ASA etc. similar renal toxicity with nonselective increase the risk of hypertension increased risk of MI and strokes PGI2 in endothelium more sensitive – aggregation by TXA2 better GIT tolerance ?? INDICATION - patients who require chronic use of NSAIDs and are at high risk for GIT toxicity

COXIBS treatment of osteoarthritis and RA ROFECOXIB, VALDECOXIB
COI in patients who are allergic to sulfonamides. avoid in patients with chronic renal insufficiency, severe heart disease, volume depletion, and/or hepatic failure. ROFECOXIB, VALDECOXIB withdrawn from market due to the increased risk of cardiovascular and cerebrovascular event upon chronic use Preferential endothelial PGI than TXA blockade Tromboembolic complications – cerebral arteries CELECOXIB [sel eh COCKS ib]

Summary of nonsteroidal anti-inflammatory agents (NSAIDs)
(according to Lippincott´s Pharmacology, 2006 Therapeutic disadvantages of selected NSAIDs Therapeutic advantages of selected NSAIDs Upper GI disturbances are common Salicylates: Low cost; long history of safety Aspirin Salicylate salts Diflunisal No antipyretic effect Less GI irritation than aspirin Acetic acids: Very potent; should be used only after less toxic agents have proven ineffective CNS disturbances common Indomethacin Sulindac Tolmetin Long half-life permits daily or twice daily dosing Propionic acids: Ibuprofen Fenorpofen Flurbiprofen Ketoprofen Naproxen Oxaprozin Lower toxicity and better acceptance in some patients. Naproxen is considered by some experts as one of the safest NSAIDs. Oxicams: Piroxicam Meloxicam Fenamates: Potential for increasing myocardial infarctions and strokes Mefenamic acid Meclofenamic acid Lower GI irritation COX-2 inhibitors Celecoxib

Number of prescriptions (million)
Reports of serious unwanted reactions to nonsteroidal anti-inflammatory (according to Rang and Dale, Pharmacology, 1995) Drug Number of prescriptions (million) Serious GIT reactions per million prescriptions Other serious reactions per million prescriptions Ibuprofen 5.47 6.6 Naproxen 4.67 32.8 8.4 Flurbiprofen 3.35 27.4 Fenbufen 1.57 35.7 33.8 Ketoprofen 3.19 33.2 5.3 Indomethacin (slow-release type) 0.44 386.4 18.2 Sulindac 1.38 23.9 30.4 Piroxicam 9.16 58.7 9.4 Diflunisal 3.13 33.5 13.7 Azapropazone 0.91 67.0 20.9

PARACETAMOL (acetaminophen)
antipyretic and analgesic It has less effect on COX in peripheral tissues, very weak/no anti-inflammatory activity. does not cause physical dependence or tolerance. it does not affect platelet function or increase blood clotting time, AE – rare at usual dosage – rash, bronchoconstriction,  blood elements

Paracetamol (acetaminophen)
Alternative for the analgesic and antipyretic effects of aspirin when gastric complaints, prolongation of bleeding time is a problem choice for children with viral infections or chickenpox Pharmacokinetics: Rapidly absorbed from the GIT a significant first-pass metabolism occurs in the intestine and liver conjugated in the liver to form inactive glucuronidated or sulfated metabolites a portion is hydroxylated to N-acetylbenzoimino-quinone – a highly reactive metabolite – it is scavanged with the sulfhydryl group of glutathione otherwise hepatotoxicity.

Metabolism of acetaminophen
HNCOCH3 HNCOCH3 HNCOCH3 Metabolism of acetaminophen Large doses of paracetamol (about 6-10 g or more in adult) - the available glutathione in the liver becomes depleted N-acetylbenzoiminoquinone reacts with the -SH of hepatic proteins, forming covalent bonds → Hepatic necrosis, a very serious and potentially life-threatening condition, can result. Renal tubular necrosis may also occur. Possibly dangerous in alcoholics. ANTIDOTE - N-acetylcysteine, which contains sulfhydryl groups to which the toxic metabolite can bind, can be lifesaving if administered within ten hours of the overdose. Sulfate OH Glucuronide Acetaminophen Cytochrome P-450 mixed function oxidase NCOCH3 Nucleophilic hepatic cell proteins Glutathione Therapeutic doses O Toxic doses Toxic intermediate HNCOCH3 Glutathione OH HNCOCH3 Mercapturic acid (nontoxic) Cell macro-molecules OH (according to Lippincott´s Pharmacology, 2009 Cell death

Clinical uses of NSAIDs
Analgesia in e.g. headache, dysmenorrhoea, backache, bony metastases of cancers, postoperative pain can reduce requirement of narcotic analgesics (e.g. Cancers) aspirin, paracetamol and ibuprofen the drugs of choice for short-term analgesia are; naproxen, piroxicam more potent, longer-acting drugs are useful for chronic pain To lower temperature paracetamol is preferred it lacks gastrointestinal side-effects and, unlike aspirin, has not been associated with Reye's syndrome in children.

Clinical uses of NSAIDs
chronic or acute inflammatory conditions e.g. rheumatoid arthritis, gout and soft tissue diseases higher dosage is required than for simple analgesia and adverse effects are common treatment is prolonged start with ibuprofen a drug with a low incidence of side-effects, more potent agents being used only if necessary. COX2-selective drug (e.g. celecoxib) for patients with a history of peptic ulcer or upper gastrointestinal bleeding There is substantial individual variability in clinical response to NSAIDs - patient preference

Oxford League Table of Analgesic Efficacy/NNTs (www. jr2. ox. ac
Oxford League Table of Analgesic Efficacy/NNTs ( pain) Valdecoxib 40 mg: Ibuprofen 800 mg: Ketorolac 20 mg/60 mg: Diclofenac 100 mg: Piroxicam 40 mg: Paracetamol 1,000 mg + codeine 60 mg: Paracetamol 500 mg + oxycodone 5 mg: Naproxen 440 mg: Ibuprofen 600/400 mg: /2.5 Aspirin 1200 mg: Paracetamol tramadol 75: 2.6 Morphine 10 mg i.m. Pethidine 100 mg i.m: 2.9

Hargreaves K, Aust Dent J 2005;50 Suppl 2:S14-S22

Neuropathic Pain Pain in absence or in addition to nociceptive component Example – trigeminal neuralgia Characteristics of pain

From: Bonica, “The Management of Pain”, 1990.

Treatment of Neuropathic Pain
Surgical Drug therapy

Drug Therapy - Neuropathic Pain
Carbamazepine Phenytoin Baclofen Gabapentin Tricylic antidepressants Local anesthetics Ketamine Clonazepam

Experimental Drug Therapy for Neuropathic Pain
N-type calcium channel blockers 2-adrenoceptor agonists (clonidine) NMDA receptor antagonists Selective serotonin reutake inhibitors Adenosine receptor agonists Valproic acid

Gout The Gout (James Gillray, 1799) depicts the pain of the artist's gout as a demon or dragon. Gout presenting in the metatarsal-phalangeal joint of the big toe: Note the slight redness of the skin overlying the joint.

Gout - therapy Options for acute treatment options for prevention
nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, steroids options for prevention XO blockade - allopurinol, febuxostat, uricosuric - probenecid uricase – pegloticase AE – allergic reaction incl serious shock, infusion reactions, acute gout exacerbation Lowering uric acid levels can cure the disease Lifestyle interventions have been poorly studied It is unclear if dietary supplements have an effect in people with gout

ANALGESICS drugs to treat pain

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