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Medical University of Sofia, Faculty of Medicine Department of Pharmacology and Toxicology OPIOID ANALGESICS © Assoc. Prof. Ivan Lambev E-mail: [email protected] Pain is the most common symptom for which patients see a doctor. Different types of drugs are used for treatment of pain. In general, they include: 1. Drugs, relieving pain due to multiple causes (analgesics) narcotic analgesics (morphine, fentanyl etc): act chiefly in the CNS non-narcotic analgesics (paracetamol, metamizole): act chiefly peripherally 2. Drugs, relieving pain due to a single cause or specific pain syndrome only They are not classified as analgesics: e.g. naratriptan (migraine), carbamazepine (neuralgias), glyceryl trinitrate (angina pectoris), adrenal steroids (inflammatory pain), butylscopolamine (spasm of visceral smooth muscles), baclofen (spasm of striated muscles) etc. 3. Adjuvant drugs (anxyolitics, neuroleptics, antidepressants) may modify the perception of pain and remove the concomitants of pain such as anxiety, fear, depression. Placebo gives relief in 3%. 4. Anaesthetics (general and local) are used during surgical operations, some diagnostic and other painful procedures. Nociception is a consequence of tissue injury (trauma, inflammation). It causes the release of chemical mediators (ACh, PGE, NA, 5-HT, glutamate, bradykinin, endogenous opioids, adenosine). They have neuronal or non-neuronal origin. These mediators activate nociceptors. Nociceptors are pain-receptors. Nociceptors transmit information by thin myelin (A-delta) and non myelin (C) fibers to the spinal cord and brain. Pain perception has a complex mechanism. It is a result of nociceptive impulses reaching the brain (thalamus, cortex), plus impulses from other peripheral receptors, e.g. heat and mechanoceptors, whose threshold of response is reduced by the same chemical mediators. These are processed in the brain whence modulated inhibitory impulses pass down to regulate the continuing afferent input. But pain can occur without nociception (e.g. some neuralgias). Pain is a psychological state, though most types of pain have a physical cause. MAIN TYPES OF PAIN Acute pain (defined as < 3 months duration) transmitted principally by fast conducting myelin A-delta fibers. It has major nociceptive input (physical trauma, pleurisy, myocardial infarction, perforated peptic ulcer). The narcotic (opioid) and sometimes non-narcotic analgesics are used for treatment of acute pain. Chronic pain (defined as > 3 months duration) is transmitted principally by slow conducting non myelin C fibers. It is better regarded as a syndrome rather than symptom. It is depressing to the patient who sees no prospect for relieving the suffering. Analgesics alone are often insufficient and adjuvant drugs (antidepressants or neuroleptics) as well as non drug therapy (including psychotherapy) have increasing importance. Neuropathic pain follows damage of the nervous system. Acute pain without nociceptive (afferent) input (e.g. some neuralgias) is less susceptible to analgesics. The suitable drugs are some antidepressants and carbamazepine. Transient pain is provoked by activation of nociceptors in skin and other tissues in absence of tissue damage. It protects humans from physical damage coming from environment or excessive stressing of tissue. It is a part of normal life and does not need treatment. HISTORY Opium is the dried juice of seed head of poppy. It was used in prehistorical times (e.g. in Egypt, Ebers’papirus – XVI b .n. c) as analgesic, tranquillizer, antitussive drug and for treating of diarrhoea. The principal active ingredient in crude opium – morphine, was isolated in 1806 from Frederic Sertűrner, who tested pure drug on himself and three young men. He observed that morphine caused cerebral depression and relieved toothache. Gay Lussac named this drug, which was the first discovered alkaloid, after Morpheus (the son of Somnus) – morphine. Papaver somniferum L. .. F. SERTURNER (1783–1841) Morphine •Opium - morphine (1806) - codeine - papaverine Afghanistan Pakistan Thailand Poppy Opium contains two groups of alkaloids: • with phenantrene structure (morphine, codeine, thebaine) • with isochinoline structure (papaverine, noscapine). Morphine and codeine are narcotic analgesic; papaverine is a vasodilator; noscapine is antitussive agent which is suspected of genotoxicity. Opium contains ≈10% morphine. Some terminology OPIOID: produces morphine-like effects. OPIATE: has a morphine-like structure. Opioid is the preferred modern term. Opioids can be divided into two groups: - Morphine analogues – with structure similar to morphine - Synthetics – with structure unrelated to morphine CH N 3 CH 3 N CH3 O HO O OH morphine CH methadone Mechanism of actions of opioid analgesics Effects are mediated via opioid receptors m (mu): mediate analgesia at the supraspinal level d (delta): analgesia in the periphery k (kappa): analgesia at the spinal level ORL1 (opioid receptor like 1): dependence There are endogenous analgesic substances with peptide structure and morphinolike action. They are called endogenous peptides and was discovered during the investigation of mechanism of analgesic action of morphine. Endogenous opioid peptides are: a) enkephalins activate μ and δ-receptors; b) endorphins activate μ, κ and δ-receptors; c) dynorphins activate μ, κ and δ-receptors. d) nociceptin – ORL1 (tolerance) Opioid peptides act in CNS as: - neurotransmitters - modulators of response (usually inhibitory) The main effects of morphine are: on the CNS Depression, leading to analgesia, respiratory depression (decrease in sensitivity of the respiratory centre to PCO2), depression of cough reflex, sleep) Excitation, leading to vomiting, miosis (pupil constriction), convulsions (very rare) Changes of mood – euphoria (sense of well being) or dysphoria. Tolerance and dependence (psychological and physical) Smooth muscle stimulation Gastrointestinal muscle spasm (with constipation) and biliary tract spasm Bronchospasm Retentio urinae Cardiovascular system Dilation of resistance and capacitance vessels Other effects Sweating, histamine release, pruritus, piloeraction, antidiuretic effect Phenomenon of Straub Tolerance and dependence Tolerance it is increasing dose of drug required to produce the same effect. It occurs rapidly with opioids (with morphine 12–24 hours, e.g. hot plate test – in mice, after 3 days dose of morphine required for analgesia increases 5-fold). Important in drug addiction – may need to increase dose 50-fold. Tolerance is not shown equally on all effects. Tolerance extends to: analgesia euphoria resp. depression To much less extent on: constipation pupil constriction This is why constipation can be such a big problem with opioids Why does tolerance occur? There are several potential reasons: - Increased metabolism of the drug - Decreased receptor affinity DEPENDENCE Takes two forms : physical psychological Physical dependence – problems include withdrawal syndrome (addiction): - Irritability - Weight loss - Shakes - Sweating - Piloeraction “cold turkey” - Effects last off in 8–10 days Psychological dependence Problems are: - Desire for the drug - Want to experience the “rush” – positive - Don’t want the withdrawal – negative - Some opioids e.g. codeine & pentazocine are much less likely to cause dependence Morphine and its analogues Morphine Hydrochloride 1% 1 ml (= 10 mg) i.m. Morphine Sulphate (Sulfate): 1 tab./12 h p.o. (depot-effect) Codeine: 10–20 mg/dose Dihydrocodeine: 1 tab./12 h p.o. (depot-effect) Oxycodone: p.o. HEROIN (diamorphine – BAN, diacetylmorphine) Similar action to morphine More active than morphine More lipid soluble – crosses BBB faster to give greater rush Shorter duration of action than morphine Synthetic derivatives PHENYLPIPERIDINES pethidine, fentanyl METHADONES methadone, dextropropoxyphene BENZOMORPHANS pentazocine THEBAINES buprenorphine, etorphine PETHIDINE (Meperidine – USAN; Lydol® – Sopharma) Almost identical to morphine Tends to cause restlessness rather than sedation Antimuscarinic effects: dry mouth blurred vision Less antitussive Shorter duration of action (4-6 h) – preferred in labour FENTANYL >80 times more potent than morphine in analgesia Main use is in anaesthesia, used in conjunction with droperidol to produce neuroleptanalgesia Effentora® – buccal tablets from 100 to 800 mcg, used in cancer BTP (breakthrough pain) Durogesic®: TTS/72 h Durogesic TTS Durogesic TTS NEUROLEPTANALGESIA •Fentanyl 100 mcg + •Droperidol 5 mg i.m. Similar to Fentanyl: •Alfentanil (NB: without “y”) •Sufentanil (NB: without “y”) METHADONE Similar actions to morphine Longer duration of action (t1/2 37 h) Less problems with withdrawal Can be used to wean heroin and morphine addicts off the drug DEXTROPROPOXYPHENE (t1/2 5 h) is structurally similar to methadone and differs in that it is less analgesic and less dependence producing. It is weak μ/κ/δ-agonist analgesics usefulness approximates to that of codeine, but its duration of action is longer. Pentazocine – κ/δ-agonist/weak μ-antagonist ETORPHINE (strong μ/κ/δ-agonist) with remarkable very high potency, more than 1000 times that a morphine. It is used to immobilize wild animals for trapping and research purposes, since require dose, even for an elephant, is small enough to be incorporated into a dart or pellet. Low efficacy for mild and moderate pain codeine, dihydrocodeine, dextropropoxiphene, oxycodone, pentazocine High efficacy for severe pain alfentanil, buprenorphine, heroin, fentanyl, methadone, morphine, pethidine, sufentanil, tramadol Tramadol – partial μ-agonist, inhibitor of NA and 5-HT reuptake. Analgesics in chronic tumour pain according to WHO 1st step: weak pain – Paracetamol 2nd step: mild pain – Paracetamol + NSAIDs 3rd step: moderate pain – Paracetamol or NSAIDs + weak opioid (e.g. Codeine or Dihydrocodeine) 4th step: strong pain – Paracetamol or NSAIDs + strong opioid (e.g. Fentanyl – Durogesic TTS, Morphine or Pethidine) OPIOID COMPETITIVE ANTAGONISTS Naloxone (μ, κ and δ-antagonist) Naltrexone (μ, κ and δ-antagonist) Nalorphine (Allylnormorphine) μ-antagonist/κ-agonist)