1. Daniel Wermeling, Pharm.D. Professor

2. Transduction Prostaglandin Tissue Injury Overall effect is increased nociceptor activation Histamine NGF Bradykinin 5-HT ATP H+ Mediators Prostaglandins Leukotrienes Substance P Histamine Bradykinin Serotonin Hydroxyacids Reactive oxygen species Substance P 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. Na/K Channel

3. Reticular Formation Rostroventral Medulla Descending Pathway Spinal Cord Ascending Pathway Dorsal Horn Primary Nociceptive Fiber (A-  or C fiber) Inhibitory Transmitters GABA Glycine Somatostatin Descending Inhibitor Pathways Excitatory Transmitters Substance P Calcitonin gene  related peptide Aspartate, glutamate 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.

4.  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

5.  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

6.  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 long- term NSAID use

8.  Morphine and cogeners  Phenylpiperidines: fentanyl, alfentanil, meperidine, sufentanil, remifentanyl  Diphenylheptanes: methadone, propoxyphene.

10.  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

11.  Butorphanol – nasal spray for migraine  Nalbuphine – rarely used  Pentazocine – rarely used  Buprenorphine – Use for pain and now for opioid detoxification

12.  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

13.  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)

14.  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

15.  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

16.  Excretion  Metabolized to glucuronides and renal elimination  Accumulate drug and metabolites in renal disease  Some metabolites, when accumulating, cause toxicity, like M3G

17.  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

18.  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

19.  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

20. 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 mg20 - 30%10-15% 100-300 mg10-20%5-10% 300-600 mg8-12%4-6 % 600-1000 mg5-10%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

21.  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

22.  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

23.  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.

24.  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

25.  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

26.  Drug seeking behavior of pain patients whose pain is inadequately treated  VS  Use of any substances for non- therapeutic purposes; or use of a medication for other than those for which it was prescribed

27.  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.

28.  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

30.  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

31.  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

32.  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

33.  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

34.  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