Pain & Pain Management: Opioids PDF

PAIN & PAIN MANAGEMENT: OPIOIDS  Pain management  Peripherally-acting  Act on peripheral pain receptors  Prevent sensitisation and discharge of the nociceptors during inflammation  e.g. NSAIDs, paracetamol, steroids  Anaesthetic agents (local and general anaesthetics)  Bl...

PAIN & PAIN MANAGEMENT: OPIOIDS  Pain management  Peripherally-acting  Act on peripheral pain receptors  Prevent sensitisation and discharge of the nociceptors during inflammation  e.g. NSAIDs, paracetamol, steroids  Anaesthetic agents (local and general anaesthetics)  Block pain signal transmission peripherally or centrally  For short-term only (long-term→ complications)  Centrally-acting  Interact with specific receptors in the CNS  Inhibit pain message and emotional responses  e.g. opioids  Rules of thumb in chronic pain  Not all pains are the same  Not all patients have the same pain sensitivities  Not all patients have the same pain relief from opioids  Not all patients have the same side effects of opioids  Not all opioids are the same  Mercadante 2001, Pasternak 2001  Terminologies  Opioid refers to any substance (endogenous or synthetic) that produces morphine-like actions that are blocked by antagonists such as naloxone  Opiate is restricted to compounds such as morphine and codeine that are found in the opium poppy  Opium is an extract of the juice of the poppy Papaver somniferum  Opioids  Morphine analogs- structure closely related to morphine  Morphine  Diamorphine (heroin)  Codeine  Nalorphine  Levallorphan  Naloxone  Synthetic derivatives  Hydromorphone (dihydromorphinone)  Pethidine  Fentanyl  Methadone  Dextropropoxyphene  Pentazocine  Buprenorphine  Etorphine  Loperamide Distinguishing Characteristics  Pharmacokinetics  Half life  Metabolism  Pharmacodynamics  Potency  Most have one or two peculiarities Endogenous Opioid Peptides Three distinct families of peptides have been identified  Enkephalins  Endorphins  Dynorphins  Each family is derived from a distinct precursor polypeptide  Opioid Receptors  7 transmembrane receptors coupled with G protein  CNS distribution is not uniform  Found in regions involved in the transmission and modulation of pain Classification of opioid receptors mu Classical delta Opioid kappa receptors Non- ORL1 classical  Modulation of pain impulse Check out this video on a good explanation of the pain processing pathways https://youtu.be/5c8maFAhqIc Descending pain pathway Brainstem local circuitry underlying the modulating effect of μ-opioid receptor (MOR)–mediated analgesia on descending pathways. The pain- inhibitory neuron is indirectly activated by opioids (exogenous or endogenous), which inhibit an inhibitory (GABAergic) interneuron. This results in enhanced inhibition of nociceptive processing in the dorsal horn of the spinal cord MoA of -opioid receptor agonists in the spinal cord Check out this video for an interesting explanation of how opioids work to inhibit pain and produce other effects https://youtu.be/t2tKyjj7u5Y Mu receptors-agonist Mu receptors- antagonist  Mu receptors- Anatomical distribution Cortex Brainstem (periaqueductal grey) Mu receptors- effects upon stimulation  Physical dependence  Euphoria  Analgesia (supraspinal)  Respiratory depression  Inhibition of GI motility  Sedation  Miosis Delta receptors-agonist Delta receptors-antagonist Delta receptors- Anatomical distribution Cerebral cortex (pontine nuclei) Delta receptors- effects upon stimulation  A nalgesia (spinal (mainly) and supraspinal)  Inhibition of GI motility  R espiratory depression (controversial experimental findings) Kappa receptors-agonist Kappa receptors-antagonist  Kappa receptors- Anatomical distribution Limbic system Brainstem (periaqueductal grey) Kappa receptors- effects upon stimulation  Sedation  Physical dependence  Analgesia (spinal)  Miosis  Dyspnea  Increased ADH (controversial) and prolactin release  Dysphoria Effects On Organ Systems CNS  Analgesia (reduce sensory and affective aspects of pain)  Euphoria (sometimes dysphoria)  Sedation (worsen when combined with other CNS depressants)  Respiratory depression (inhibit brainstem resp. mechanism)  Cough suppression  Miosis (also mediated by parasympathetic pathway)  Truncal rigidity  Nausea and vomiting (activate brainstem CTZ) Peripheral effects  Bradycardia  Constipation  Biliary colic  Decreased renal plasma flow  Prolong labor  Stimulate the release of ADH, prolactin, somatotropin  Pruritus OPIOID AGONISTS/ANALGESICS  Phenanthrenes Morphine, hydromorphone, oxymorphone, heroin Phenylheptylamines Methadone Strong agonists Phenylpiperidines Fentanyl, sufentanil, alfentanil, meperidine Morphinans Levorphanol Phenanthrenes Codeine, oxycodone, Opioid agonists dihydrocodeine, hydrocodone Phenylheptylamines Mild-moderate agonists Propoxyphene Phenylpiperidines Diphenoxylate, difenoxin, loperamide Weak agonists Tramadol Strong opioid agonist: MORPHINE MoA  Acts at µ opioid receptors (MOR) in the dorsal horn of spinal cord which modulates pain transmission  Inhibits the release of excitatory transmitters from nerve terminal carrying nociceptive stimuli Effects  Analgesia  Euphoria  Respiratory depression  Cough suppression  Miosis – K and µ receptors, apparent in morphine abusers  Emesis- stimulation of CTZ  Decrease motility of the intestine  Hypotension & bradycardia- at large doses, CI in severe brain injury because it will cause dilation of cerebral vessels and increase CSF pressure (when + resp. depression)  Histamine release from mast cells- CI in asthma  Inhibit the release of hormones  Prolong labour CNS effects Morphine analgesia **reduces both sensory and affective aspects of pain experience  severe cancer pain is tolerated more when person is given morphine  relieves all types of pain, but most effective against continuous dull aching pain  sharp, stabbing, shooting pain are also relieved by morphine Morphine given to a pain free individual:  first experience is dysphoria  Usually it is not experienced in person in pain Morphine sedation  morphine causes sedation effect, but no loss of consciousness, no amnesia  supplements BDZ when pain is present and sleep is necessary Morphine euphoria  sense of well being  reason why morphine is abused Effects of morphine on respiration Inhibition of brainstem respiratory mechanisms- decreased response to CO2 There is a primary and continuous depression of respiration related to dose  decrease rate  decrease volume  decrease tidal exchange  mu receptor activation produces respiratory depression; with increase in dose can cause further respiratory depression  CNS becomes less responsive to pCO2 thereby causing a build up of CO2  rhythm and responsiveness causes irregular breathing patterns; one will see periods of apnea Cardiovascular effects  Cardiovascular effects of morphine lead to vasodilation, thus a decrease in blood pressure due to:  morphine causes the release of histamine and  suppression of vasomotor-stabilizing mechanisms and  suppression of reflex vasoconstriction Morphine effects on the gastrointestinal system  increase in tone and decrease in mobility leads to constipation – action on enteric nervous system  decreased concentration of HCl secretion  increased tone in stomach, small intestine, and large intestine  delay of passage of food (gastric contents) so more reabsorption of water  **tolerance does not develop (i.e. same amount of effect each time) to this constipation effect Pupil size  morphine causes miosis (pinpoint pupils)  kappa receptor effect  pinpoint pupils still responsive to bright light  occulomotor nerve (CN3) is stimulated by kappa receptor site  if kappa receptor is blocked, mydriasis from sigma effect will result  atropine partially blocks effect indicating parasympathetic system is involved Therapeutic uses  Analgesia- very effective  Acute pulmonary edema- IV----vasodilation--- relieves dyspnea  Relief cough –codeine and dextrometorphan are more widely used  Diarrhea  Applications in anesthesia- sedative, anxiolytic and analgesic properties; used as premed, intraoperatively or as a primary component Pharmacokinetics Absorption  readily absorbed from GI tract, nasal mucosa, lung subcutaneous, intramuscular, and intravenous route Distribution  bound free morphine accumulates in kidney, lung, liver, and spleen  CNS is primary site of action (analgesia/sedation) but only a small percentage crosses BBB (the least lipophilic) Morphine administration  oral morphine rarely given due to erratic oral availability  significant variable first pass effect from person to person and have intraspecies effect (same dose will vary in person day to day)  IV morphine acts promptly and its main effect is at the CNS Metabolism/excretion  metabolic transformation in liver  conjugation with glucuronic acid  excreted by kidney  half life is 2.5 to 3 hours (does not persist in body tissue)  morphine 3 glucuronide in main excretion product  lose 90% in first day  duration of 10 mg dose is 3 to 5 hours Acute overdose  High doses (overdose situation) of morphine  excitatory and spinal reflexes  high doses of many OPIOID cause convulsions  due to stimulation at sigma receptor Tolerance to morphine  nausea  analgesia  sedation  respiratory depression  euphoric not to:  miosis  constipation Toxicity of morphine  acute overdose  respiratory depression  pinpoint pupils (miosis)  coma Treatment  1. establish adequate ventilation  1a. 4 point restraints needed  2. give OPIOID antagonist (naloxone)  Drug interactions with Opioids **in general, the coadministration of CNS depressants with OPIOID often produces at least an additive depression (potentiation) Strong agonists  Hydromorphone and oxymorphone- for treating severe pain  Hydromorphone  Synthetic “sister” of morphine  Potency is 5x morphine  Widely available in multiple forms: oral pill and liquid, pills, parenteral  More rapid onset and shorter half-life  Heroin  Potent  Fast-acting  Highly addictive  Similar efficacy to morphine in relieving severe chronic pain Codeine, morphine, hydromorphone metabolism Glucuronidation 10% of codeine becomes morphine Morphine and hydromorphone are both glucuronated to active metabolites. Increased efficacy is usually associated with an increase in addiction liability of an opioid  Methadone  Potent analgesic, potent µ-receptor agonist  Also block non-opioid receptors- NMDA receptors and monoaminergic reuptake transporters → relieve neuropathic, cancer pain when morphine therapy failed  Suppress symptoms of opioid withdrawal  Long t1/2  Tolerance and physical dependence develop slowly, mild withdrawal symptoms  RoA: oral, iv, sc, spinal and rectal  Fentanyl  Subgroup-sufentanil, alfentanil, remifentanil  Potency: sufentanil >>> fentanyl > alfentanil  Remifentanil- rapidly metabolised by esterases, very short t1/2  Used in anaesthesia practice  Meperidine  Significant antimuscarinic effects- C/I tachycardia  Negative inotropic action  Accumulation of normeperidine may produce seizure  Levorphanol  Synthetic opioid  Similar action to morphine Mild to moderate agonists  Codeine, oxycodone, dihydrocodeine, hydrocodone  Partial agonists  Note: Codeine is not an analgesic unless metabolized to morphine  Up to 10% of population are poor metabolizers – little or no analgesia from codeine  Rapid metabolizers also may have little analgesia  Less efficacious than morphine as analgesic  More adverse effects at doses used to produce analgesia  Usually combined with aspirin, PCM  Propoxyphene  Chemically related to methadone  Low analgesic activity  Low abuse liability  Low efficacy-not suitable for severe pain Effects of codeine  Diphenoxylate, difenoxin (metabolite)  Used in the treatment of diarrhea  Low abuse liability  Used in combination with low dose of atropine  Loperamide  Used in the treatment of diarrhea  Limited access to the brain  Very low abuse liability Weak agonist  Tramadol  Centrally acting  Weak µ-receptor agonist  MoA: block serotonin reuptake, inhibit NA transporter  Partially antagonised by naloxone  SE: seizure, nausea, dizziness  CI in patients with epilepsy and for use with other drugs that lower seizure threshold  Adjunct in the treatment of chronic neuropathic pain Common adverse effects of opioids Drug interactions Opioid withdrawal symptoms Opioids with Mixed Receptor Actions  Agonist  Partial agonist  Antagonist Equianalgesic conversion (relative potency of analgesics as compared to oral morphine) To understand the concept of equianalgesia, check out this video https://youtu.be/3BnZKiJqzew OPIOIDS WITH MIXED RECEPTOR ACTIONS & OPIOID ANTAGONISTS Opioids with Mixed Receptor Actions e.g. nalbuphine, buprenorphine, butorphanol, pentazocine  Nalbuphine  Strong K receptor agonist, µ receptor antagonist  Given parenterally  used to treat moderate to severe pain  May cause withdrawal symptoms in individuals dependent on narcotics  Respiratory depression not reversible with naloxone  Buprenorphine  Partial µ receptor agonist  Potent, long-acting (slow dissociation from µ receptors)  Significant first pass effect- sublingual  Resistant to naloxone reversal  Relieve the symptoms of opiate withdrawal  Used in the management of opioid dependence  Butorphanol  Produces analgesia equivalent to nalbuphine and buprenorphine but more sedation  K receptor agonist, µ receptor partial agonist or antagonist  Pentazocine  K receptor agonist, weak µ receptor partial agonist or antagonist  Oral or parenteral Opioid Antagonists  Pure opioid antagonists- naloxone, naltrexone, nalmefene  High affinity for µ binding site  Reverses opioid effects within minutes but inert in opioid free individuals  Inert in the absence of opioid agonists Naloxone  Given by injection (high first pass effect)  Short duration of action  Used in the treatment of acute opioid overdose-can cause relapse into coma after 1-2 hours  At low dose- treatment of adverse effects associated with iv or epidural opioids  Suboxone ® - buprenorphine + naloxone  Naltrexone  Long duration of action  Orally active  An alternative to methadone in the treatment of addiction to heroin and other opiates  Nalmefene  Given iv only  Used in opioid overdose  Longer duration of action Homework EQUI-ANALGESIC POTENCIES OF OPIOIDS  Compare the efficacy (to produce analgesia) of other opioids to morphine  Opioid rotation or switching - may be considered if a patient obtains pain relief with one opioid and is suffering severe adverse effects  Converting from one opioid to another-the initial dose depends on the relative potency of the two drugs and RoA  An individualised approach is necessary  Conversion factors are an approximate guide only – significant interindividual variations