1. Neuraxial Opioid-Induced Pruritus Tariq Alzahrani Demonstrator College of Medicine King Saud University

2. Definition Is a sensation that provokes the desire to scratch & can be aroused by variety of mechanical, electrical & chemical stimuli. It is bothersome to the patient & sometimes may be more unpleasant than pain itself for the patient.

3. Incidence It is varies from 30% to 100%. Parturients appear to be the most susceptible, reported between 60% & 100% & appears to be dose-dependent. This increased incidence may be due to an an interaction of estrogen with opioid receptors. In orthopedic surgery between 30% & 60%

4. Pathophysiology The sensation of itch arises from the superficial layers of the skin, the mucous membranes & the conjuctivae. Based on microstimulation studies, the current view is that nerve endings in the subepidermal area cluster densely around itch points that correspond to areas that are very sensitive to pruritogenic stimuli in humans.

5. Postulated the C fiber may represent the afferent units mediating itch sensation. The exact mechanism of neuraxial opioid-induced pruritus is unclear.

6. Postulated mechanisms include : -The presence of an itch center in the CNS -Medullary dorsal horn activation -Antagonism of inhibitory transmitters -Modulation of the serotoninergic pathway -Involvement of prostaglandins

7. The presence of an itch center in the CNS Koenigstein has described the presence of an itch center in the lower medulla that includes the trigeminal nucleus. Injection of high doses of morphine(0.2 to 1mg/kg) into the cisterna cerebellomedullaris of cats induced itch behavior. Intracisternal injection of alizarin blue produced itch & stains in depth only the lower part of the medulla oblongata.

8. Antagonism of inhibitory neurotransmitters Opioid antagonism of GABA & glycine in the CNS. Intrathecal administration of the glycine antagonist strychnine in cats produces similar itch & scratch behavior as large doses of intrathecal morphine.

9. Medullary dorsal horn activation & serotonin Morphine produces part of its analgesic effect through the release of serotonin. There are dense concentration of serotonin receptors in the dorsal part of spinal cord & the nucleus of spinal tract of the trigeminal nerve in the medulla, in which opioid receptor density is also high. These observations suggest that the 5-HT receptor may be implicated in the development of the pruritus associated with neuraxial opioid.

10. Prostaglandins PGE1 & PGE2 enhance C fiber transmission to the CNS. They are also known to release histamine & to potentiate pruritus induced by histamine.

11. Co-administration of epinephrine may have an influence on spinal & epidural opioid-induced pruritus.

12. Prevention & Treatment Pharmacologic agentMechanismSite of action Opioid antagonistMue-receptor inhibitionMedullary dorsal horn, nucleus trigeminalis PropofolDepression of nerve transmission Medullary dorsal horn NSAIDsCyclooxygenase enzyme inhibition Endoplasmatic reticulum of macrophages DroperidolDepression of nerve transmission 5-HT3 receptor inhibition Medullary dorsal horn, nucleus trigeminalis 5-HT3 antagonist5-HT3 receptor inhibitionMedullary dorsal horn, nucleus trigeminalis

13. Conclusion Although pruritus after neuraxial administration of opioids is a common side effect, to date few studies have elucidated the mechanisms, mediators, neural pathways & pathophysiology of this symptom. A better understanding of the pathophysiology would lead to improved preventative & treatment strategies.

14. In the management of neuraxial opioid- induced pruritus we recommend that minimal analgesic doses of opioids should be used to provide pain relief during & after surgical operation.

15. 5-HT3 receptor antagonists (ondansetron) the drug of choice due to : -Minimal side effects ( headach ) -No effect on the quality of analgesia -Ability to prevent & treat potoperative nausea & vomiting With multiple pathways involved in the pathophysiology of pruritus, combination therapy should be examined.