Strategies for Acute Pain Management in Patients on Extended-Release Naltrexone

1. Strategies for Acute Pain Management in Patients on Extended-Release Naltrexone Megan T. Mitchell, PharmD PGY1 Pharmacy Resident UConn John Dempsey Hospital May 8th, 2018 Eastern States Residency Conference

2. Disclosure • I have no conflict of interest to report • I intend to reference unlabeled/unapproved uses of drugs or products in my presentation

3. Learning Objectives • List the FDA-approved indications for the use of extended-release naltrexone • Identify appropriate non-opioid analgesic treatment options beyond the standard of care, for the management of severe, acute pain in patients on extended-release naltrexone injectable suspension

4. Extended-Release Naltrexone(ERN) • Once monthly intramuscular injection • Indications • Treatment of alcohol dependence • Treatment of opioid dependence following detoxification • Opioid antagonist • Highest affinity for the mu opioid receptor • Extended Release Naltrexone Injectable Solution [package Insert]. Waltham, MA: Alkermes, Inc. 2015

5. Pharmacokinetics of ERN • Duration of action of ERN is approximately 28 days • Important to assess the time of last injection • The blockade is surmountable with high dose opiates • Increased risk of respiratory depression and death • Extended Release Naltrexone Injectable Solution [package Insert]. Waltham, MA: Alkermes, Inc. 2015

6. Challenges of using ERN • Patient education is essential • Patients should be highly self-motivated • Risk of overdose if using higher doses than before • Willingness to communicate to other providers • Adherence to once monthly injection schedule • Provider education

7. Challenges of using ERN • Currently no universal method for identifying these patients • Altered mental status or unconscious • Not dispensed through retail pharmacy • Not reported on PMP • Access to EMR is often limited • Stigma related to use • Highly encourage patients to utilize medical alert bracelets/tags

8. Elective Procedures • Appropriate communication between healthcare professionals is key • Track dates of administration • Schedule elective procedures to fall as close to day 28 as possible • Opioids can be used for acute post-op pain

9. Standard of Care for Managing Acute Pain

10. Standard of Care • Acetaminophen • NSAIDs • Skeletal muscle relaxants • Baclofen, cyclobenzaprine, tizanidine • Anticonvulsants • Gabapentin, pregabalin • Benzodiazepines • Diazepam, midazolam, lorazepam, alprazolam

11. Clinical Question What strategies are available to treat severe, acute pain if these standard of care methods are not providing adequate relief and opioids are not an option?

12. Ketamine • A non-competitive NMDA and glutamate receptor antagonist with potent analgesic, anxiolytic and amnestic properties • Rapid onset of action • Preserves airway patency, ventilation and cardiovascular stability 1. White PF, Way WL, & Trevor AJ: Ketamine - its pharmacology and therapeutic uses. Anesthesiology 1982; 56:119-136. 2. Ketamine hydrochloride injection solution [package Insert]. Lake Forrest, IL: Hospira Co. 2004

13. Ketamine • Anesthetic dosing • 1- 4.5 mg/kg bolus • 0.5 mg/kg/min • Sub-dissociative dosing • 0.2-0.8 mg/kg bolus • 0.1-0.3 mg/kg/hrcontinuous infusion • Titration based on pain control and signs of CNS/CV side effects • White PF, Way WL, & Trevor AJ: Ketamine - its pharmacology and therapeutic uses. Anesthesiology 1982; 56:119-136. • Gurnani A, Sharma PK, Rautela RS, et al: Analgesia for acute musculoskeletal trauma: low-dose subcutaneous infusion of ketamine. Anaesth Intensive Care 1996; 24:32-36 • Ketamine hydrochloride injection solution [package Insert]. Lake Forrest, IL: Hospira Co. 2004

14. Dissociation and Emergence • Dissociation: patient passes into a trance like state • At the doses used for pain, this side effect is less common • Emergence: gradual return of consciousness after discontinuing administration of an anesthetic • May be accompanied by psychotomimetic effects PerumalDK, Adhimoolam M, Selvaraj N, Lazarus SP, Mohammed MAR. Midazolam premedication for Ketamine-induced emergence phenomenon: A prospective observational study. Journal of Research in Pharmacy Practice. 2015;4(2):89-93.

15. Ketamine • Risks to consider • Increased BP and HR • Respiratory depression • Following rapid IV pushes of high doses • Diplopia or nystagmus • Slightly elevated intraocular pressure • Enhanced skeletal muscle tone • Manifested by tonic-clonic movements Ketamine hydrochloride injection solution [package Insert]. Lake Forrest, IL: Hospira Co. 2004

16. Peripheral Nerve Blocks (PNB) • Continuous PNB vs. Single shot PNB • Used for localized injuries • Performed by injection of the anesthetic adjacent to a nerve or nerve plexus of interest Girish Joshi. “Peripheral nerve blocks in the management of postoperative pain: challenges and opportunities.” Journal of Clinical Anesthesia, 10 Aug. 2016. Pubmed, Accessed 23 Aug. 2017

17. Peripheral Nerve Blocks • Can contain many combinations of drugs • Local anesthetics • Corticosteroids • Sodium bicarbonate • Epinephrine • Often contain an opioid for additional analgesia • Avoid in patients on ERN

18. Additives • Sodium Bicarbonate • Used to decrease the time to onset of a block by ensuring molecules are in their uncharged, basic form to cross the nerve membrane • Epinephrine • Vasoconstrictor to slow absorption into tissues which can decrease toxicity and prolong duration of block • Corticosteroids • May help to prolong analgesia after PNB Neal JM, Gerancher JC, Hebl JR, et al. Upper extremity regional anesthesia: essentials of our current understanding, 2008. RegAnesth Pain Med 2009; 34:134.

19. Peripheral Nerve Blocks • Risks to consider • Perineural hematomas • Neurologic complications • Tingling, pain on pressure, pins and needles • Local anesthetic systemic toxicity (LAST) • Dose-dependent • Metallic taste, tinnitus, perioral numbness, seizure, cardiac arrest, death Girish Joshi. “Peripheral nerve blocks in the management of postoperative pain: challenges and opportunities.” Journal of Clinical Anesthesia, 10 Aug. 2016. Pubmed, Accessed 23 Aug. 2017

20. Epidural with Local Anesthetics • Can be used for anesthesia of abdomen, pelvis, and lower extremities • Performed by placing a catheter into the epidural space • Using the same combinations of anesthetic and adjuvants as used in peripheral blocks • Veering BT, Cousins MJ. Epidural neural blockade. In: Cousins & Bridenbaugh's Neural Blockade in Clinical Anesthesia and Pain Medicine, 4th ed, Cousins MJ, Carr DB, Horlocker TT, Bridenbaugh PO (Eds), Lippincott Williams & Wilkins, Philadelphia 2009.

21. Epidural with Local Anesthetics • Post Dural Puncture Headache (PDPH) • Frontal or occipital headache • Within 6 to 72 hours of the procedure • Occurs due to inadvertent puncture of the dura • Results in leakage of cerebral spinal fluid • Headache can last 2 - 15 days without treatment Kuntz KM, Kokmen E, Stevens JC, et al. Post-lumbar puncture headaches: experience in 501 consecutive procedures. Neurology 1992; 42:1884.

22. Treatment of PDPH • Epidural blood patch • Blood is injected epidurally at or near the site of the prior LP • Volume replacementand sealing of the CSF leak • Alternate therapies • The limited available data suggest modest effectiveness for gabapentin, hydrocortisone, and theophylline BoonmakP, Boonmak S. Epidural blood patching for preventing and treating post-dural puncture headache. Cochrane Database Syst Rev 2010; :CD001791. 27.Sandesc D, Lupei MI, Sirbu C, et al. Conventional treatment or epidural blood patch for the treatment of different etiologies of post dural puncture headache. ActaAnaesthesiolBelg 2005; 56:265.

23. Technique • Injection into epidural space vs. around peripheral nerve plexus • Technique is important • Inappropriate placement can be dangerous and very uncomfortable for the patient

24. Barriers to Epidural Use • Coagulation status • Sepsis or infection at the site • Increased intracranial pressure • Low platelet count • Uncorrected hypovolemia • Anesthesiologists may be required to follow patient until epidural is removed

25. Test Your Knowledge Which of the following is not an FDA approved indication for the use of Extended-Release Naltrexone? • Alcohol dependence • Opioid dependence • Opioid detoxification • All of the above

26. Test Your Knowledge Which of the following is not an FDA approved indication for the use of Extended-Release Naltrexone? • Alcohol dependence • Opioid dependence • Opioid detoxification • All of the above

27. Test Your Knowledge Which of the following doses of ketamine is appropriate for the management of severe pain in a patient who is on ERN and arrives at the ED with a broken femur s/p MVA? • 0.2-0.8 mg/kg bolus followed by 0.1-0.3 mg/kg/min • 1- 4.5 mg/kg bolus followed by 0.5 mg/kg/min • 0.2-0.8 mg/kg bolus followed by 0.1-0.3 mg/kg/hr • 1- 4.5 mg/kg bolus followed by 1 mg/kg/hr

28. Test Your Knowledge Which of the following doses of ketamine is appropriate for the management of severe pain in a patient who is on ERN and arrives at the ED with a broken femur s/p MVA? • 0.2-0.8 mg/kg bolus followed by 0.1-0.3 mg/kg/min • 1- 4.5 mg/kg bolus followed by 0.5 mg/kg/min • 0.2-0.8 mg/kg bolus followed by 0.1-0.3 mg/kg/hr • 1- 4.5 mg/kg bolus followed by 1 mg/kg/hr

29. Take Home Points • Identify appropriate non-opioid analgesic treatment strategies for the management of severe, acute pain in patients on ERN • Providing pain relief is challenging • Use combinations of medications • Educate patients and other providers • Utilize an interprofessional approach

30. Strategies for Acute Pain Management in Patients on Extended-Release Naltrexone Megan T. Mitchell, PharmD PGY1 Pharmacy Resident UConn John Dempsey Hospital memitchell@uchc.edu