1. Plasma concentration Time PO: C max ~ 60 minutes (oxymorphone ~ 30 minutes ) SQ: C max ~ 30 minutes IV: C max ~6 minutes Pharmacologic administration curves after single opioid dose

2. PRN dosing interval based on time to C max: 1 mg hydromorphone iv Q 10 minutes prn 1 mg hydromorphone sq Q 15-30 minutes Despite these efforts Fred continues to have uncontrolled pain. How rapidly can you safely escalate his continuous infusion and his prn dose? PRN dosing interval based on time to C max: 1 mg hydromorphone iv Q 10 minutes prn 1 mg hydromorphone sq Q 15-30 minutes Despite these efforts Fred continues to have uncontrolled pain. How rapidly can you safely escalate his continuous infusion and his prn dose? Opioid infusionsDose escalation

3. Adjust bolus dose by up to 100% at least every 30-60 minutes until effective Adjust infusion rate by up to 100% based on prn need every 12-24 hours Adjust bolus dose by up to 100% at least every 30-60 minutes until effective Adjust infusion rate by up to 100% based on prn need every 12-24 hours

4. The pain crisis 40 year old man with rectal cancer S/P abdominoperineal resection Wound dehiscence Hospitalized for > 100 days Daily c/o severe pain Prescribed 2 mg hydromorphone q 1 hour prn pain Uncertain how much he had actually been receiving 40 year old man with rectal cancer S/P abdominoperineal resection Wound dehiscence Hospitalized for > 100 days Daily c/o severe pain Prescribed 2 mg hydromorphone q 1 hour prn pain Uncertain how much he had actually been receiving

5. The pain crisis Time Hydromorphone mg Response 13002None 13104None 13154None 13308None 13428None 135516None 141516Partial 143016Good/Drowsy Total74 mg over 90 minutes

6. Methadone

7. Dual effect Mu-opioid receptor antagonist (analgesia) NMDA antagonist (prevention/reversal of opioid tolerance) Variable equianalgesic ratios Dual effect Mu-opioid receptor antagonist (analgesia) NMDA antagonist (prevention/reversal of opioid tolerance) Variable equianalgesic ratios

8. Methadone 24 hr oral morphine 0-30 mg 31-99 mg 100-299 mg 300-499 mg 500-999 mg > 1000 mg PO Morphine: Methadone ratio 2:1 4:1 8;1 12:1 15:1 20:1 24 hr oral morphine 0-30 mg 31-99 mg 100-299 mg 300-499 mg 500-999 mg > 1000 mg PO Morphine: Methadone ratio 2:1 4:1 8;1 12:1 15:1 20:1

9. Methadone Dual affect Mu-opioid receptor antagonist (analgesia) NMDA antagonist (prevention/reversal of opioid tolerance) Variable equianalgesic ratios Variable metabolism Half life 8 to 190 hours Plethora of drug-drug interactions Dual affect Mu-opioid receptor antagonist (analgesia) NMDA antagonist (prevention/reversal of opioid tolerance) Variable equianalgesic ratios Variable metabolism Half life 8 to 190 hours Plethora of drug-drug interactions

10. Methadone Potent Effective Cheap Complicated Dangerous Potent Effective Cheap Complicated Dangerous

11. Fentanyl IV:Transdermal =2:1 Fentanyl IV: Morphine IV roughly 100:1 Transdermal absorption dependent on fat stores IV:Transdermal =2:1 Fentanyl IV: Morphine IV roughly 100:1 Transdermal absorption dependent on fat stores

12. Side effects Constipation Up to 80 % of patients Requires stimulant laxatives Does not abate with time Counseling important Nausea Transient Vestibular mediated Responds to anticholinergic anti-emetics Ondansetron is NOT an anticholinergic antiemetic Educate patients Constipation Up to 80 % of patients Requires stimulant laxatives Does not abate with time Counseling important Nausea Transient Vestibular mediated Responds to anticholinergic anti-emetics Ondansetron is NOT an anticholinergic antiemetic Educate patients

13. Side effects Pruritis Transient, responds to antihistamines. Histamine release is pharmacologic property of morphine Often misinterpreted as allergic reaction Urinary retention Rare but potentially serious Pruritis Transient, responds to antihistamines. Histamine release is pharmacologic property of morphine Often misinterpreted as allergic reaction Urinary retention Rare but potentially serious

14. Side effects Sedation Especially with initiation or dose increase Usually resolves More common with elderly, high dose, polypharmacy Responds to Adjuvants/dose reduction Opioid rotation Stimulants Marked sedation requires evaluation Sedation Especially with initiation or dose increase Usually resolves More common with elderly, high dose, polypharmacy Responds to Adjuvants/dose reduction Opioid rotation Stimulants Marked sedation requires evaluation

15. Neurotoxicity

16. Opioid neurotoxicity 55 yo old woman with breast cancer Pain initially controlled on dilaudid 10 mg/hour Over the past 10 days pain has worsened despite increase in dilaudid to 50 mg/hr. Patient is anxious, restless. Complains of pain “all over” Pain elicited by gently stroking arm Occasional twitching of chest wall and leg noted. 55 yo old woman with breast cancer Pain initially controlled on dilaudid 10 mg/hour Over the past 10 days pain has worsened despite increase in dilaudid to 50 mg/hr. Patient is anxious, restless. Complains of pain “all over” Pain elicited by gently stroking arm Occasional twitching of chest wall and leg noted.

17. Opioid metabolism Morphine is metabolized in the liver to: Morphine-6 glucuronide (Active) Morphine-3 glucuronide (Neuroexictory) Excreted in the kidney Morphine-3-glucuronide accumulates in renal failure, high dose and prolonged therapy, oliguria Morphine is metabolized in the liver to: Morphine-6 glucuronide (Active) Morphine-3 glucuronide (Neuroexictory) Excreted in the kidney Morphine-3-glucuronide accumulates in renal failure, high dose and prolonged therapy, oliguria

18. Opioid neurotoxicity Increasing sensitivity to pain (hyperalgesia) Worsening pain despite rapid opioid escalation Pain becomes diffuse Delirium, hallucinations Allodynia, myoclonus, seizures Increasing sensitivity to pain (hyperalgesia) Worsening pain despite rapid opioid escalation Pain becomes diffuse Delirium, hallucinations Allodynia, myoclonus, seizures

19. Opioid neurotoxicity Risk factors: High dose Morphine>hydromorphone>oxycodone, fentanyl, methadone Renal failure Oliguria Can occur at any dose Risk factors: High dose Morphine>hydromorphone>oxycodone, fentanyl, methadone Renal failure Oliguria Can occur at any dose

20. Opioid neurotoxicity Management Prevention, anticipation, early recognition Assess urine output, magnesium level, electrolyte abnormalities Hydration if otherwise appropriate Opioid rotation at 25% equianalgesic dose Add NMDA antagonist (ketamine or methadone) Benzodiazepines/phenobarbital based on severity Prevention, anticipation, early recognition Assess urine output, magnesium level, electrolyte abnormalities Hydration if otherwise appropriate Opioid rotation at 25% equianalgesic dose Add NMDA antagonist (ketamine or methadone) Benzodiazepines/phenobarbital based on severity

21. Opioid refractory pain

22. Causes of opioid refractory pain Rapid progression cancer New source of pain Abscess Occult fracture Bladder outlet obstruction Pain refractory to opioids (Neuropathic pain, skin ulceration) Opioid related Malabsorption, Drug diversion Toxicity Fear, existential or spiritual pain Delirium Rapid progression cancer New source of pain Abscess Occult fracture Bladder outlet obstruction Pain refractory to opioids (Neuropathic pain, skin ulceration) Opioid related Malabsorption, Drug diversion Toxicity Fear, existential or spiritual pain Delirium

23. Opioid refractory pain- Management Opioid rotation or dose escalation Use of adjuvants, non-opioids NMDA antagonists (Ketamine and/or methadone) Address spiritual and psychologic concerns Non-pharmacologic treatments Interventional modalities, radiation therapy if appropriate Consideration of palliative sedation Opioid rotation or dose escalation Use of adjuvants, non-opioids NMDA antagonists (Ketamine and/or methadone) Address spiritual and psychologic concerns Non-pharmacologic treatments Interventional modalities, radiation therapy if appropriate Consideration of palliative sedation

24. Barriers to pain relief Clinician related Health care system related Patient related Clinician related Health care system related Patient related

25. Reluctance to report “The good patient” Fear of not receiving chemotherapy Reluctance to treat Fears of tolerance Fear of addiction Stigma Meaning of pain Side effects “A tradeoff between managing the pain and managing the consequences of managing the pain” Reluctance to report “The good patient” Fear of not receiving chemotherapy Reluctance to treat Fears of tolerance Fear of addiction Stigma Meaning of pain Side effects “A tradeoff between managing the pain and managing the consequences of managing the pain”

26. Supporting patient adherence Normalize concerns “Some patients worry about becoming addicted or the drug not working in the future when you need it. Are these of concern to you?” Non-judgmental questioning: “It must be really hard to take all these pills. How often, in the last week, have you found that you forget one or two?” Educate and follow up on likely side effects Normalize concerns “Some patients worry about becoming addicted or the drug not working in the future when you need it. Are these of concern to you?” Non-judgmental questioning: “It must be really hard to take all these pills. How often, in the last week, have you found that you forget one or two?” Educate and follow up on likely side effects

27. “Pain is a multifaceted phenomenon involving not only a tissue damage response but also psychological, social, spiritual and existential domains. (Nessa Coyle, JPSM, 2004) “Pain is a multifaceted phenomenon involving not only a tissue damage response but also psychological, social, spiritual and existential domains. (Nessa Coyle, JPSM, 2004)