Declarations

1. Declarations No conflicts of interest Will discuss off-label use of medications

2. What does “off-label” mean? • Use for an indication which is not by in the (FDA) approved labeling (product insert) • Legal? • Yes, but provider must • Be well informed about the product • Base it’s use on firm scientific rationale & sound medical evidence • Maintain record of the use & effects FDA, retrieved 4/02/2001: http://www.fda.gov/RegulatoryInformation/Guidances/ucm126486.htm

3. OIP, here we go again Joe Dietrick, CRNA, M.A. Have A Nice Day Anesthesia, LLC Chillicothe, MO

4. Objectives • Review possible mechanisms of neuraxial OIP • Discuss prevention strategies • Dosing of intrathecal & epidural medications • Discuss treatment options • Prophylaxis • Management

5. Who & what • Ideal • long-term post-op pain control • ∅ adverse effects • Incidence1 • Overall 30 – 100% • Obstetric 60 – 100% •  estrogen ↔ opioid receptors   OIP • Rats:  itching & pain with estrogen injection3 • High on list of patient dis-satisfaction issues2 • Dose-dependent • Intrathecal Morphine – greatest offender

6. Where, why, & how • Etiology: “unclear”4 “not fully understood”5 • Not histaminic • Postulated sites1: • Itch center in CNS • Antagonism of inhibitory transmitters • Dorsal horn activation

7. http://www.mayoclinic.org/trigeminal-neuralgia/enlargeimage2871.htmlhttp://www.mayoclinic.org/trigeminal-neuralgia/enlargeimage2871.html Where, why, & how • Trigeminal nucleus in brainstem1 • Itch receptors  facial sensation • Neuraxial  Cephalad spread • IV  CSF • Many opioid receptors • Extension of Substantia gelatinosa • Not reversible with Naloxone • Tested with cats!2

8. Where, why, & how • Numerous mediators implicated5 • High [5-HT3] serotonin receptors • Trigeminal nucleus • Dorsal spinal cord • D2 receptors • Both epidural & IV Droperidol have (+) effect • Others, less well documented • Prostaglandins: Diclofenac & Ketorolac • GABA or glycine receptors

9. AA metabolism - review http://www.mydietaryfats.org/index.php/site/content/C33/

10. http://www.neuropinc.com/technology.html Where, why, & how • Neurogenic itch – central opioid receptors5 (+)μ (medullary dorsal horn) (–)Κ & δ • Multiple studies • Mid-Brain • Spinal cord

11. An ounce of prevention… • Does spinal Bupivacaine effect OIP6? • Dose:Response study, N = 42 • CSE, Fent 10 mcg & MorphPF 0.2 mg • Bupiv: 1 mg increments: 6 – 12 mg (6/group) • No differences in pruritus • Also, found 11 mg optimal dose (60’ duration)

12. An ounce of prevention… • MorphPF – epidural7 • Dose:Response study, N = 60 • Lido 2% / Epi 1:200k, ≥ 20 ml • 1.25 mg increments: 0 – 5 mg • All doses > 0 mg  pruritus • No signif diff between doses or severity • 3.75 mg • optimal degree/duration •  side effects

13. An ounce of prevention… • MorphPF – intrathecal8 • Dose:Response study, N = 100 • Hyperbaric Bupivacaine, 7.5 mg • 0.1 mg increments: 0 – 0.4 mg • OIP: linear  in proportion to dose • 0.1 mg “comparable” analgesia to other doses

14. So… what do we use? • Classes fit receptors (believed to be) affected • Opioid receptor antagonists • Mixed agonist-antagonists • 5-HT3 antagonists • D2 agonists • NSAIDs • Propofol • More studies on prevention vs. treatment

15. Did I forget to mention… • Anti-histamines? • Effective for systemic histaminic triggers5 • Parenteral Morphine • Not an opioid-receptor effect • Use… at best • Sedative • Anti-emetic

16. μ Receptor Antagonists • Naloxone(Narcan) • IV Bolus • 40 – 80 mcg9 • ½ life ≈ 45 – 90’  repeat doses • Infusion10 • 0.25 – < 2 μg/kg/hr • 0.6 μg/kg/hr best balance? • Naltrexone (Revia, Vivitrol) • 6 mg orally (3, 6, 9 mg groups, 1990) • ½ life – 4 hrs. Active metabolite – 13 hrs.

17. Mixed agonist/antagonists • μantagonists, Κagonists11 • Ko & Song (2003):K stimulation  ↓ pruritus • Butorphanol (Stadol)11 • Low affinity for μreceptors • ↑K affinity  ↑ sedation • Nalbuphine(Nubain) • 3 – 10mg IV • Titration study: 2-3 mg optimal; 4mg ↑ pain5 • “Rarely necessary to give more than two 5 mg doses…9

18. 5-HT3 antagonists • Yeh et al (2000): MorphPF 0.15mg for CS Treatment group% pruritus Ondansetron 0.1 mg/kg 25% Control & Diphenhydramine ≈ 85%

19. 5-HT3 antagonists • Bonnet et al (2008)12 • Systematic review • 15 trials evaluated (n=1337) • “Modestly” reduced • Pruritus • Intensity • PONV • Rescue treatment

20. 5-HT3 antagonists

21. 5-HT3 antagonists • George et al (2009)15 • Systematic Review & Meta-analysis • Only CS with IT Morphine (0.1 – 0.2 mg) • 9 trials, N = 1152 • Didn’t significantly reduce incidence; but… •  severity (NNT = 12) •  need for treatment (NNT = 15) • Treatment (1 study) • Ondansetron 4 mg IV (vs. Control) • Severity score 3-4 decreased to 1-2: 80% (vs 36%)

22. 5-HT3 antagonists • Bonnet et al vs George et al

23. D2 agonists • Droperidol: also weak 5-HT3 antagonism1 • Doses vary, including epidural administration • 1.25 – 5 mg • Kjellberg & Tramer (2001) systematic review10 • 2.5 mg IV effective • 5 mg IV (or 2.5 mg Epid) not different from control • Different studies, different results • Several studies: (+) effectiveness in prevention5

24. Propofol • ↓ posterior horn transmission1 • Mixed results in studies • Borgeat (1992): 10 mg IV (q 5’ x 3 prn)9 • Relief: 84% vs 16% control • Rapid relief DOA > 60 mins • Kjellberg & Tramer (2001) – 3 prevention studies10 • Only effective regime • 10 mg bolus + 30 mg/hr infusion IV • 20% pruritus vs. 60% Intralipid (control)

25. NSAIDs? • Diclofenac100 mg rectally9 • IT morphine, not obstetric • Reduced pruritus, & ↓ pain • Ketorolac: Pavy et al (2001)13 • CS: CSE w/Fentanyl12.5 mg IT • TX: Ketorolac30 mg IV post- delivery • + 120 mg over 24 hrs • pruritus (N, Tx vs Control) • 12 hr: 9 vs 17 • 24 hr: 0 vs 11

26. Comparative studies • Naloxone0.2 mg vs Nalbuphine5 mg IV9 • Nalbuphine: ↓ pruritus & pain, ↑ sedation • Naloxone: more doses, ↑ pain scores • Another study: infusions of each  similar results5 • Naloxone2 μg/kg vs Propofol10 mg • Equal itching relief, ↓ pain in propofol group

27. Comparative studies • Sequential studies by same group • CS: Morphine 0.2 mg IT • Nalbuphine3mg vs Propofol20 mg IV5 • Initial success (10’): 83% vs 61% • ↑ recurrence 1st 4° with Propofol • Nalbuphine4 mg vs Ondansetron4 / 8 mg IV14 • Pts requesting treatment for pruritus • Group N-4O-4O-8Placebo • %: 25 47 51 72

28. Comparative studies • Horta et al (2006) 300 CS patients5

29. Is prophylaxis effective? • Most studies: prevention vs management • Most studies: further research needed • No cost-effectiveness studies • No drug with marked effectiveness • Nearly all have some potential side effect

30. Treatment options • Simple • Education • Avoid “scratching” & subsequent injury • Cold compresses • Nursing staff comfort levels • Lower threshold with familiarity?

31. Bring it home: my best guess • Treatment probably better than prevention • Nalbuphine 2.5 – 5 mg IV; repeat 3 – 6 °prn • Acute severe • Propofol 10 – 20 mg IV • Naloxone 40 – 80 mcg IV • Drugs you were probably giving anyway • Ketorolac • Ondansetron • Droperidol 1.25 mg IV – comfort level?

32. References • Szarvas et al (2003). Neuraxial opioid-induced pruritus. Journal of Clinical Anesthesia, 15:234 –239. • Toomey, M. & Biddle, C (2006). Itching, the “little” big problem as an orphan syndrome. AANA Journal, 74(5):379-384. • Nag, S.; Mokha, S. S. (2004). Estrogen attenuates antinociception produced by stimulation of Kölliker–Fuse nucleus in the rat European Journal of Neuroscience, (20)11:3203-3207. • Ayuoub, C. & Sinatra, R. PostOperative Analgeasia: Epidural & Spinal Techniques. In Chestnut, D. (Ed), Obstetric Anesthesia, Principles & Practice, 3rd Ed ( Pg 472-503). • Ganesh, A & Maxwell, L (2007). Pathophysiology & Management of Opioid-Induced Pruritus. Drugs, 67(16):2323-2333. • Ginosar, Y, et al (2004). ED50 and ED95 of Intrathecal Hyperbaric Bupivacaine Coadministered with Opioids for Cesarean Delivery. Anesthesiology, 100(3): 676-682. • Palmer, C et al (2000). Postcesarean Epidural Morphine: A Dose-Response Study. Anesth Analg, ;90:887–91. • Girgin, N (2008). Intrathecal morphine in anesthesia for cesarean delivery: dose-response relationship for combinations of low-dose intrathecal morphine and spinal bupivacaine. Journal of Clinical Anesthesia 20:180–185. • Ayoub, C. & Sinatra, R. (2004). Postoperative Analgesia: Epidural & Spinal Techniques. In Chestnut, D. (Ed), Obstetric Anesthesia, Principles & Practice, 3rd Ed ( Pg 488-489) . • Kjellberg, F. & Tramer, M. (2001). Pharmacological control of opioid-induced pruritus. European Journal of Anaesthesiology, 18:346–357. • Stoelting, R. (1991). Pharmacology & Physiology in Anesthetic Practice. Philadelphia: J.B. Lippincott Co. • Bonnet, M. et al (2008). Effect of prophylactic 5-HT3 receptor antagonists on pruritus induced by neuraxial opioids: a quantitative systematic review. British Journal of Anaesthesia,101(3):311-319. • Pavy, T. et al (2001). The Effect of Intravenous Ketorolac on Opioid Requirement and Pain After Cesarean Delivery. Anesth Analg 92:1010–4. • Charuluxananan et al (2003). PREVENTION OF INTRATHECAL MORPHINE-INDUCED PRURITUS. Anesth Analg 96 (6): 1789. • George, R. et al (2009). Serotonin Receptor Antagonists for the Prevention and Treatment of Pruritus, Nausea, and Vomiting in Women Undergoing Cesarean Delivery with Intrathecal Morphine: A Systematic Review and Meta-Analysis. Anesth Analg 109 (1) July: 174-182.