Mai Nguyen Mercer University COPHS Doctor of Pharmacy Candidate 2012 October 27, 2011 Preceptor: Dr. Ali Rahimi

 During the past two decades, the under- treatment of acute pain has been widely recognized as an important issue in health care.  Estimated that only ¼ of surgical patients in the US received adequate relief of acute pain.  Why there has been little progress in the treatment of acute postoperative pain is still unclear but the causes might be multifactorial.

 Mechanisms  Incision pain differs in its mechanism from other inflammatory or neuropathic pain.  Thought to be mediated by:  Sensitization of Aδ-fiber and C-fiber nociceptors  Conversion of mechanically insensitive or silent Aδ nociceptors to mechanically sensitive fibers after incision  Increased lactate concentrations and low pH in skin and muscle wounds after incision  Increase in prevalence and rate of spontaneous activity of spinal dorsal horn neurons

 Predictors of Postoperative Pain  Preoperative pain  Anxiety  Young Age  Obesity  Surgical fear  Type of surgery and duration  Thought that early identification of predictive risk factors will help in development of effective pain management programs.

 Acute Opioid-Induced Hyperalgesia (OIH)  Paradoxical response to opioids in which patients who receive opioids could actually become to painful stimuli  leads to hyperalgesia rather than analgesia.  Caused by the upregulation of pronociceptive pathways within the central and peripheral nervous systems. ▪ Activation of glutamate and N-methyl-D-aspartate (NMDA) receptors  Distinctly different from analgesic tolerance to opioids, which results from desensitization of antinociceptive pathways. ▪ Although both will ultimately result in an increase in opioid requirements.  Occur in low, high, and maintenance doses of opioids  Reported treatment of acute OIH: ▪ α 2 agonists, COX-2 inhibitors, NMDA receptor antagonists (mostly studied) more sensitive

 Genetics-based Pain Therapy  Determination of a patient’s genotype to personalize pain therapy. CYP2D6OPRM1PTGS2SCN9A  Over-expression: ↑ metabolism of tramadol and morphine  Under-expression: inhibit the prodrug activation of codeine to morphine  Mutation at 118A  G leads to reduction in μ- opioid receptor expression and signaling  Associated with differences in individual responses to COX-2 inhibitors  Production of ABCB1 (glycoprotein) - identification of patients susceptible to respiratory depression induced by opioids.  Mutation reported in individuals with complete inability to sense pain

 Persistent Postsurgical Pain (PPP)  Diagnosed when pain persists beyond expected healing period associated with tissue injury and inflammation and other causes for pain have been excluded ▪ 2 months or longer after most surgical procedures  Many common operations (mastectomy, hernia repair, coronary artery bypass surgery, amputation) are associated with incidence of PPP of up to 30-50%.  Risk factors: perioperative pain, old age, female sex, obesity, depression, duration of disability (time to return to work)  Prevention of PPP: COX inhibitors, α 2 agonists, gabapentin, NMDA antagonists, and steroids

Common routes of admin Probable MOAPotential SEs Local anesthetics (bupivacaine, lidocaine) EA/SA, PNB/C, SC, TR Inhibition of sodium channel Hypotension, systemic toxicity – seizures, cardiac dysrhythmias, cardiac arrest Opioids (fentanyl, morphine) EA/SA, IV, SC, TR μ-receptor agonistSedation, N/V, respiratory depression Paracetamol PO, IV UncertainHepatic toxicity and liver failure at high doses, hypersensitivity NSAIDs (Celebrex, ibuprofen, ketorolac) PO, IV Inhibition of cyclo- oxygenase GI irritation, platelet inhibition, renal insufficiency or failure Gabapentinoids (gabapentin, pregabalin) PO Inhibition of voltage- gated sodium channels Sedation, peripheral edema α 2 agonists (clonidine, dexmedetomidine) PO, IV α 2 –receptor agonistSedation, hypotension, bradycardia EA/SA = epidural/spinal, PNB/C = peripheral nerve block/catheter, TR = transdermal, SC = subcutaneous

 Extended-release local anesthetics  Currently, researchers are developing local anesthetics encapsulated in various biodegradable agents (liposomes, lipospheres, polyglycolic acid microspheres, and hydrogels), which when degraded will allow the gradual release of anesthetics.  None of formulations are currently available.

 Extended-release epidural morphine  DepoDur® is an extended-release formulation of epidural morphine, which is enclosed in microscopic lipid-based particles. ▪ Provides postoperative pain relief for 48 hours after a single dose ▪ Typical duration of epidural morphine is 12 to 24 hours. ▪ Increased incidence of respiratory depression when compared with IV patient-controlled analgesia with morphine.

 Iontophoretic transdermal delivery of fentanyl  Traditional transdermal formulation of fentanyl is not recommended for routine treatment of acute or postoperative pain in opioid-naïve patients ▪ Partly because it can take about 6-12 hours to obtain analgesic plasma fentanyl concentrations after application  IONSYS™ uses low-intensity direct current (iontophoresis) to allow for a more rapid transfer of fentanyl from the patch into the skin and local circulation. ▪ Allows the patient to activate a demand dose of 40 μg of fentanyl with a lockout interval of 10 mins ▪ Withdrawn voluntarily from market due to technical challenges.

 Peripherally acting μ-opioid receptor antagonists  Opioids used to treat acute pain can exacerbate postoperative ileus.  Peripherally acting μ-opioid receptor antagonists (methylnaltrexone and alvimopan) have been developed to avoid the adverse effects of opioids on postoperative ileus while providing analgesia.  Some concern with alvimopan in its association with a raised incidence of MI in one study.  Role of these agents in treatment of acute pain has yet to be established, but they might be of benefit to patients who have postoperative paralytic ileus.

 Acupuncture  Review incorporating 15 randomized controlled trials noted a significant decrease in opioid consumption, risk of opioid-related SEs (eg, nausea), and postoperative pain intensity with adjunctive use of perioperative acupuncture.  TENS  Relaxation therapy  Massage  Hypnosis  Listening to music Associated with reduction of pain and opioid requirement when used as adjunctive therapy

 Postoperative pain remains incompletely controlled in some settings and the reasons why are not entirely clear.  Development of newer and more effective analgesic agents and techniques provide superior analgesia with a reduction in persistent pain states and improve patient outcomes.