1 Analgesics opioids (anodynes) Pain - types A) According to length of experience 1) acute: sign of and disease, danger or damage to organism... 2) chronic: more than 3 months/ unusually long for and given disease Breakthrough pain: sudden pain in chronic background drug-controlled pain (typically in progression of cancer) B) According to pathophysiology 1) Nociceptive – irritation of nociceptors Therapy: „analgesic ladder“ 2) Neurologic: Therapy: psychopharmacs (antidepressants) and anticonvulsants 3) Psychogennic: Therapy: psychopharmacs (antidepressants – TCA, SSRI) Pain - types Pharmacologic modulation of pain Analgesics – antipyretics Analgesics – anodynes (opioids) Local anaesthetics General anaesthetics Adjuvant therapy (antidepressants, antiepileptics anticonvulsants, antimigrenics, corticoids, caffeine…) Pharmacologic modulation of pain Adjuvant therapy: Bone pain: biphosphonates, corticoids Neuropathic pain: antidepressants, antiepileptics, anticonvulsants Visceral pain: spasmolytics, corticoids Analgesics Analgesics – anodynes (opioids) Analgesics – suppress perception of pain (increase the pain threshold) selectively without influencing perception of other stimuli Non-opioid analgesics On spinal and supraspinal level Effects on somatic and visceral pain Strong effects on consciousness Mostly peripheral effects Effects on inflammation Weaker effects in general No effects on visceral pain No addiction 2 Analgetics - anodynes Block transmission of pain signal among CNS (cells brain, spinal cord) by binding to opioid receptors (agonists) Similarly to endogenous opioids : endorphins, enkephalins, dynorphins Opiates natural compounds with effects similar to morphine Opioids + synthetic and semi-synthetic substances Opioid receptors - μ κ δ (σ) G-protein coupled, i. adenylylcyklase, facilitate opening of K+ channels postsynaptically, inhibit opening of Ca 2+ channels presynaptically μ - supraspinal analgesia, euphoria, sedation, miosis, breath depression, addiction, GIT effects κ – spinal + peripheral analgesia, sedation, dysphoria, miosis, GIT δ – spinal analgesia, breath depression, GIT [σ – dysphoric effects (anxiety, hallucinations)] Opioid receptors - μ κ δ (σ) μ - supraspinal analgesia FOR ANALGETIC EFFECTS IS CRUCIAL ACTIVATION OF RECEPTORS: κ – spinal + peripheral analgesia Pharmacological influention on opioid receptors agonists (mostly μ and κ) parcial agonists – dualists (high affinity to μ with low IA - buprenorphin) mixed agonists – antagonists (agonist on κ, antagonist on μ - pentazocin) antagonists (affinity to μ and κ without IA – naloxon, metyl-naltrexon) + atypical opioid tramadol – effect on μ + 5HT + NOR Central effects of opioids • analgetic • supression of center of breathing • sedation • supression of anxiety • euphoria/dysphoria • antitussic effect • nausea and vomiting • increased tendency to convulsions/cramps • miosis • ↑secretion of ADH, ↓ GnRH, corticotropine, FSH, LH, ACTH 3 GIT ↑tonus, ↓motility pro-spasmogennic effects Urinary sys. ↑tonus of sphincter, ↓detrusor urine retention (especially after surgery) Kidneys decreased perfusion and GF Peripheral effects of opioids KVS vasodilatation - orthostatic hypotension tachycardia Uterus ↓ tonus, motility, elongation of labor Mast cells histaminoliberation Bronchi, oviduct inhibited function of cilliar epithelium Side effects in clinical management: • Depression of breath centre – the most feared • Nausea and vomiting – 30 – 80% of patients on the beginning of the therapy • Sedation, depression of cognitive functions • Constipation – about 50 % of patients (or more) • Itching Rapid toleration evolves for most of these effects with exception of constipation Comparison with non-opioid analgetics Advantages No: parenchym toxicity gastropathy hematotoxicity Effect on coagulation Useful in polymorbidity Disadvantages individual tolerability and efficacy typical AE addictiv potential imunosupression ↓ endocrine functions PHARMACOKINETICS ABSORPTION – parenteral p.o. – first pass effect perrectal transdermal DISTRIBUTION – parenchymatous organs muscles fat tissue (lipophilic, e.g. fentanyl) brain (fentanyl, heroin…) Can cross placental barrier!!! BIOTRANSFORMATION - liver – CYP 450 → polar metabolites, conjugates - inactive metabolites - active metabolites (codein, tramadol) EXCRETION - urine - bile 4 Weak opioids n Weak agonists on μ (codein, dihydrocodein) n Atypical opioid tramadol n Mixed agonist – antagonist - agonist on κ, antagonist on μ (pentazocin) Ceiling effect – further increase of dosing does not lead to increased analgetic effects Intermediate and weak opioid agonists Codein, dihydrocodein 10 % mtb. to morphin weak analg., better in combinations (e.g. with paracetamol – Ultracod, Talvosilen) ↓ risk of addiction KI - CHOPN Codeine - antitussic in subanagetic doses Dihydrocodeine – often constipation Atypical opioid Tramadol low affinity for μ receptors + blocked reuptake of noradrenaline and increased release of serotonin about 1/6 of morphin analgesia – relatively weak, usually combined with paracetamolem AE – often dizziness and nausea serotonine syndrom (in combination with SSRI) Tramal, Tralgit, Noax UNO Agonist - antagonist Pentazocin Not suitable for CHP Lots of psychomimetic effects Strong opioids n full agonists for μ n For strong resistant pain n No ceiling effect, doses recommended in pharmacopoeia are often not enough, progressive dosing is necessary n indications: cancer pain, dorzalgia, neuropatic pain, revmatic pain, osteoarthrosis morphin selective µ agonism cca 10 % of opium, together with codeine + other phenantren alkaloids n p.o. (with slow release - MST Cont) – for CHP n parent. (i.v., i.m., s.c., epidural, intrathek.) – AP n effervescent tablets – fastest onset – BP n p.rect. administration Disadvantages – AE, cumulation of toxic metabolites – in renal insuff, elderly people, dehydration 5 Fentanyl pure μ agonist for strong CHP lipophilic – very well pass HEB and mucoses (100x higher potency than morphin) TTS – 3-day release with very stable levels in plasma, less AE Fentanyl-citrate – orally or nasally aplied on mucoses, rapis effect in 5 min – BP disadvantage – it is necessary to titre the dose individually Hydromorphon relatively safe opioid in p.o. retarded preparations (12 or 24h) for therapy of CHP Oxycodon Preparation with 2-phase release – at first bolus and than slow 12 hours release – for strong CHP, neuropatic pain Metabolism via 2D6 to active metabolites – in fast metabolisers strong effect and vice versa Combination with naloxone (antagonist) suppress constipation Parc. agonists / agonists - antagonists Buprenorphin parc. agonist on μ, antagonist on κ rcp. advantages – lower addiction potential and less AE disadvantages - lower analgesic effects - first pass effect → inj., sublingual, TTS - ceiling effect indications - analgesic - therapy of opioid addiction Pethidin/meperidin (Dolsin, Demerol) • ↓ suppression of breathing centre and lower spasmogenic effect than morphin • toxic metabolite norpethidin causes myoclonal convulsions and cramps → p.o. and parenterally in AP • interaction with IMAO • today less advantageous parenteral opioid Piritramid Inj. in strong AP (eg. after surgery) Metadon Substitution in addiction treatment Heroin - diacetylmorphin Antagonists of opioid analgesics naloxon, naltrexon Indications: treatment of intoxication, respiration depression, diff. dg. of addiction ! New preparation in combination with opioids methylnaltrexon – peripheral antagonist Intoxication by opioids nausea, flush, hučení in uších, tinnitus apathy, sedation, sleep, miosis superficial breathing cyanotic, cold skin, rapid heart rate asfphyxia Therapy - naloxon i.v. - ventilation, vital functions - in unconsciousness parenteral liquids TRIAS: coma, breath supression, miosis 6 Rotation of opioids n Switch in case of AE n Sometimes even in equianalgesic dose increase of effect n Lately methadon is started to be used (cheap, long half-life, no active metabolites) Other indications n Antitussic effect n In dry not-productive cough - u codeine n Constipative effect n Premedication in general anesthesia n Calms down the patient and by means of synergism decreases the total dose of narcotics used (what increases safety of general anaesthesia) n Most often fentanyl and its derivates n Combination of analgesic anodyne with neuroleptic (eg. fentanyl + droperidol) in case of neuroleptanalgesia THALAMONAL inj. n Substitution therapy in heroin or other opiates/opioid addiction– methadon, buprenorphin Rules of pain therapy management n Choice and course of analgetic therapy depends on intensity and character of pain described by the patient – individual dosing – titration may take weeks in CHP n Acute pain – course - from up going down – start with strong medication (opioid), parenteral administration, fast onset (eg. pain in AIM, renal or biliar colic) n In chronic pain – course – from down going up – non-invasive preparations (p.o., TTS), slower release according to a time plan n In some types of fluctuating chronic pain it may be necessary to give patient rescue medication in case of breakthrough pain n Combination of non-opioid and opioid analgesics has additive effect n Benefits of analgesic therapy should exceed its side effects. n AE must be prevented rather than treated when they appear – eg. antiemetics, diet, laxatives n There is not a maximal dose of opioid – (in case of full agonists and cancer pain) n Rotation of opioids Morphini hydrochloridum trihydricum i.v., i.m., s.c. DTS: 0,005-0,02 p.o. DTS: 0,01-0,02 (! I více) p. rect. DTS: 0,015-0,03