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Daniel Wermeling, Pharm.D. Professor Transduction Substance P Tissue Injury Prostaglandin Histamine NGF Bradykinin Mediators • Prostaglandins • Leukotrienes • Substance P • Histamine • Bradykinin • Serotonin • Hydroxyacids • Reactive oxygen species 5-HT ATP H+ Na/K Channel Kelly D, et al. Can J Clin Anaesth. 2001;48:1000-1010. Pain: Current Understanding of Assessment, Management, and Treatments. Monograph developed by NPC and JCAHO, December 2001. Overall effect is increased nociceptor activation Reticular Formation Rostroventral Medulla Descending Pathway Primary Nociceptive Fiber Excitatory Transmitters • Substance P • Calcitonin generelated Ascending peptide Pathway • Aspartate, glutamate (A- or C fiber) Dorsal Horn Inhibitory Transmitters Spinal • GABA Cord Descending • Glycine • Somatostatin Kelly D, et al. Can J Clin Anaesth. 2001;48:1000-1010. Pain: Current Understanding of Assessment, Management, and Treatments. Monograph developed by NPC and JCAHO, December 2001. Inhibitor Pathways MOA – inhibit prostaglandin synthesis, via cyclooxygenase (COX) – peripheral and central COX-1 produces metabolites that relate to platelet aggregation and GI cytoprotection, renal function (constitutive) COX-2 - inducible by inflammatory stimulus and mediates pain, inflammation and fever Acetaminophen Inhibits brain much more that peripheral COX Produces analgesia and antipyrexia Poor anti-inflammatory Good analgesic for acute mild to moderate nociceptive pain, generally well tolerated First line therapy for low back pain and osteoarthritis Acute and chronic dosing limits of 4gm/d 2.8gm/day for elderly Hepatic necrosis & kidney damage Re-examination of utility of chronic use in fixed-dose combination products Analgesic, antipyretic and anti-inflammatory Relative COX 1-2 blockade per drug All produce similar analgesic effects yet there is wide inter-patient variability Individual response varies to each one Give 2-3 week trial Oral meds and IV ibuprofen and IM and nasal spray ketorolac Lose cardioprotective effects of aspirin and COX-2 inhibition may increase risks of MI Use GI cytoprotectives concurrently for longterm NSAID use Morphine and cogeners Phenylpiperidines: fentanyl, alfentanil, meperidine, sufentanil, remifentanyl Diphenylheptanes: methadone, propoxyphene. Provide analgesia via activation of opioid receptors in CNS; similar to action of endogenous endorphins Appear to have some effects in periphery Products activate or block mu, delta and kappa receptors Differences in physical chemical properties and binding affinity account for variable physiologic effects Agonist, partial agonist, agonist-antagonist, antagonist Butorphanol – nasal spray for migraine Nalbuphine – rarely used Pentazocine – rarely used Buprenorphine – Use for pain and now for opioid detoxification Naloxone – Customary IV antagonist, short acting, opioid antidote 5% oral bioavailability Injection adapted for nasal spray in emergency Nalmefene – newer longer acting IV antagonist, moderate duration, oral availability Naltrexone – oral opiate antagonist, long duration – used in maintenance of detoxification & alcoholism treatment Produce analgesia, CNS depression, respiratory depression in a dose dependent manner Depress neurogenic drive and decrease response to increased carbon dioxide Cough suppression, miosis, hypothermia, nausea and vomiting, histamine release, bronchoconstriction, increased smooth muscle tone (bladder, GI tract) Physical-chemical properties ADME Absorption – highly variable across products Oxycodone, hydrocodone, methadone excellent absorption Morphine 25-50% absorption – first pass metabolism Lipophilicity affects rate of absorption Distribution – widely distributed Speed of onset/offset correlates with lipophilicity See fentanyl as example Metabolism Morphine and others subject to high first pass (is saturable) Codeine requires CYP2D6 to activate to morphine Heroin is de-acetylated to morphine Morphine has active metabolites (M6G), others may not have actives, and M3G produces hyperalgesia and hyperactivity Excretion Metabolized to glucuronides and renal elimination Accumulate drug and metabolites in renal disease Some metabolites, when accumulating, cause toxicity, like M3G Hydromorphone has less N & V and histamine release Kappa agonists have ceiling effect for analgesia and resp. depression Methadone also NMDA receptor antag. Meperidine – neurotoxic metabolite Fentanyl et al. – chest-wall rigidity Less potent analgesic Not considered first-line agent because of high potential for adverse events Patients develop tolerance quickly Should not be used for more than 1 or 2 days Avoid use in elderly, renal impaired Useful IV to treat pain and post-operative shivering in the PACU A mainstay of treatment for opioid maintenance Growing use for treating chronic pain Usage for acute versus chronic pain differs Single dose, onset of 10-20 min., t1/2 of 24 h + (variable) and analgesia duration of 4-8 hours Chronic - Accumulates with repeated dosing; incomplete cross tolerance with opiates, may require dosage reduction or increased dosing intervals. Need a week to see full effect of dosage changes Careful evaluation required – Increased Qtc; cardiac arrythmia as risk on top of standard risks Used in opioid rotation - due intolerable SE or tolerance to other opioids Many respiratory arrest deaths also reported with methadone use due to inexperience Total Daily Oral Morphine Dose Estimated Daily Oral Methadone Dose as % of Total Daily Oral Morphine Dose* Estimated Daily IV Methadone as % of Total Daily Oral Morphine Dose* <100 mg 20 - 30% 10-15% 100-300 mg 10-20% 5-10% 300-600 mg 8-12% 4-6 % 600-1000 mg 5-10% 3-5% > 1000 mg <5% <3 % * Daily dose must be divided into a dosing schedule for administration, i.e., divide by 2 for twice a day dosing Approximately 100 times more potent than morphine or 100 mcg ~ 10 mg IV morphine Significant first-pass metabolism, reducing effect of oral administration Very lipophilic, quick onset, seconds to minutes, short half-life due to redistribution Don’t get on hands – it is absorbed IV use in anesthesia Delivery systems include patch, buccal tablet, nasal spray and lozenge Most common problem is use of opiates with other drugs that cause significant sedation in their own right Promethazine and other phenothiazines Benzodiazepines/Skeletal muscle relaxants Alcohol THC Antidepressants and Antipsychotics Co-administration is the most common way patients die from use of opioids Physiologic state of neuro-adaptation that is seen as withdrawal symptoms when the drug used is reduced or discontinued or an antagonist administered. This is an expected outcome from chronic opioid use. This is not addiction. Generally over-excitation as a result of removing an inhibitor Rhinorrhea Lacrimation Piloerection Hyperthermia and chills Muscle aches Emesis, diarrhea, cramping Anxiety, agitation, hostility Insomnia Tachycardia and hypertension Need for an increased dose to maintain same level of analgesia This represents neural adaptation It usually develops slowly once acceptable analgesia in obtained Need for a higher dose could easily represent under treatment of pain Tolerance also develops to many opioid untoward effects This is not addiction Drug seeking behavior of pain patients whose pain is inadequately treated VS Use of any substances for nontherapeutic purposes; or use of a medication for other than those for which it was prescribed A neurobehavioral syndrome resulting in psychological dependence on the use of substances for the psychic effects and is seen as compulsive use despite the harms being caused. Physical dependence and tolerance are normal consequences of extended opioid therapy and are not addiction. Block re-uptake of NE and SE & Na+ channel Enhances pain signal inhibition Tricyclics are a first line agent Prefer secondary amine to tertiary amines Desipramine, nortriptyline Less side effects Take at night to lower side effects and enhance sleep SN/SRI’s help depression and some analgesia Duloxitene, and SNRI, approved for diabetic peripheral neuropathy Modulators of peripheral nerve and spinal cord pre- and post- ganglionic receptors Ion channel (Na/Ca) modulators/blockers GABA inhibitors Older medications include phenytoin, carmbazepine, too toxic New medications Gabapentin Pregabalin Capsaicin Cream (Zostrix) (hot pepper enzyme) MOA – depletes substance P from C-nerve endings with chronic use Start with lower concentration first Apply 3-4x/day to effect Substantial burning on application and some don’t tolerate this, but tolerance does develop Don’t get on eyes or mucus membranes Uses – Peripheral neuropathy, post-herpetic neuralgia and arthritis MOA – sodium channel blockade of nerve fibers Infiltration injection will block pain in the dermatomal distribution Injection into periphery or into CSF EMLA (lidocaine & prilocaine) cream and Lidocaine patch for neuropathic pain Reduce activation of NMDA receptors which are involved in chronic nociceptive and neuropathic pain Include: Amantadine: Neuropathic pain, low risk of side effects Memantine: Neuropathic pain (animal studies) Ketamine: Neuropathic pain and preemptive analgesia Dextromethorphan: Neuropathic pain and preemptive analgesia; high doses needed, variety of side effects Methdadone – dual mechanism of action Understand the mechanisms of pain signal generation, transmission and modulation Pharmacology of various agents affect different aspects of pain signaling Link nature of injury to choice of agent(s) Many agents have additive analgesia & different SE profile – good combinations Choose agents to fit patient specific needs, comorbidity, and concurrent-meds