#280

Dexmedetomidine

  • Kasey Malotte PharmD
  • Kathryn Walker PharmD
  • Drew A Rosielle MD

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Background      Dexmedetomidine (Precedex) is a relatively new drug with sedative and analgesic properties.  It is FDA approved for short-term sedation of non-intubated patients undergoing surgery or a medical procedure or in intubated patients in the intensive care unit (ICU) unit. There has been increasing interest in its use in end-of-life settings. This Fast Fact reviews dexmedetomidine’s use relevant to palliative care. 

Pharmacology     Dexmedetomidine is an intravenous, relatively selective, alpha-2 adrenergic receptor agonist. In the ICU, its FDA approved use is only up to 24 hours, however, published reports indicate it is being used for longer periods (1-3).  It can be given as a infusion (e.g., for ventilator sedation) or a bolus (e.g., for procedural sedation). Its onset of action is 5-10 min, peak affect 15-30 min, with duration of action of 60-120 min after a bolus. It is 94% protein bound and metabolized in the liver to renally excreted metabolites. Its elimination half-life in healthy adults is ~2 hours (4). Besides sedation and analgesia, its major clinical effects are related to the generally sympatholytic effects of alpha-2 agonism: bradycardia and hypotension. When administered at standard infusion rates, a transient increase in blood pressure often occurs followed by a sustained lower blood pressure of ~10-20% below baseline (5). Unlike most sedatives, it is not known to suppress respiratory drive at clinically relevant doses (6,7).

Clinical Findings – Mechanically Ventilated Patients     There has been much interest in investigating dexmedetomidine’s promise as a superior sedative for mechanically ventilated patients in the ICU. Results have been mixed as to whether it provides a meaningful improvement over other agents, notably benzodiazepines and propofol. Some studies have shown dexmedetomidine use is associated with less delirium, shorter ICU lengths of stay, and decreased time to extubation (8-13), but these finding have not been universal (10). Compared to propofol and midazolam, at any given level of sedation, dexmedetomidine does improve patients’ ability to communicate pain (8,11). In all these studies, bradycardia was found to be significantly worse in dexmedetomidine patients compared to benzodiazepines or propofol.

Clinical Findings – Pain     Sub-sedating doses of dexmedetomidine have been used as an analgesic, although there are no controlled clinical trials investigating this specific use. Two case reports in patients with severe, refractory cancer pain found the temporary use (~3-6 days) of dexmedetomidine at 0.2-0.6 mcg/kg/hour greatly reduced the patient’s pain, while alternative analgesic modalities were explored (1,14). There has also been an intriguing case series published, describing the use of dexmedetomidine for suspected opioid-induced hyperalgesia (OIH; see Fast Fact #142) (3). In this case series, patients on high-dose opioids with suspected OIH were transferred to the ICU, if not already there, and given dexmedetomidine at rates of 0.2-0.7 mcg/kg/hour for 2-7 days. Coincident with initiating the infusion, opioid doses were decreased, and on average patients’ opioid doses were decreased by ~70% with apparently equal or better analgesia. The authors note they suspect dexmedetomidine “’reboots’ opioid sensitivity,” although the true mechanism of action for this effect, if even real, has not been determined.

Clinical Findings – Symptoms at the End-of-Life     Given the observation that patients sedated with dexmedetomidine appear to remain more arousable and interactive compared to patients sedated with benzodiazepines, there has been interest in using dexmedetomidine to manage delirium as well as provide sedation, anxiolysis, and analgesia for patients with severe symptoms near the end-of-life, while avoiding the need to deeply sedate patients to unconsciousness (see Fast Facts #106, 107) (14,15). One case series indicated some success with this practice (15). In this series, boluses of 1 mcg/kg were used, followed by infusions of 0.2-0.6 mcg/kg/h for 5-48 hours. A pilot-study is underway to further investigate this use of dexmedetomidine (16), but currently there are no more data to guide clinicians.

Cost: Dexmedetomidine is available in a 200 mcg vial for $55.00 (17).  For comparison midazolam is available in a 5 mg vial for $5.00 and propofol in a 200mg vial for $10.00 (17,18).  Thus, dexmedetomidine is ~3-4 times more expensive than midazolam and propofol. 

Summary     Dexmedetomidine is a unique sedative, and there is interest in its use as an analgesic and for end-of-life symptom control. Its expense, need for close monitoring during its use (including, for most institutions, ICU monitoring), and lack of controlled clinical trials, currently prohibit any recommendation for its use outside of the ICU setting.

References

  1. Roberts SB, Wozencraft CP, Coyne PJ, Smith TJ.  Dexmedetomidine as an adjuvant analgesic for intractable cancer pain.  J Palliat Med. 2011;14:371-3.
  2. Roukonen E, Parviainen I, Jakob S, et al. Dexmedetomidine versus propofol/midazolam for long-term sedation during mechanical ventilation. Intensive Care Med. 2009;35:282-90
  3. Belgrade M, Hall S. Dexmedetomidine Infusion for the Management of Opioid-Induced Hyperalgesia.  Pain Med. 2010:1-8. 
  4. Precedex [package insert]. Lake Forest, IL: Hospira, Inc; 2012
  5. Gertler R, Brown HC, Mitchell DH, Silvius EN. Dexmedetomidine: a novel sedative-analgesic agent.  BUMC Proceedings. 2001;14:13-21
  6. Venn RM, Hell J, Grounds MR. Respiratory effects of dexmedetomidine in the surgical patient requiring intensive care.  Crit Care.  2000;4:302-8.
  7. Ebert T, Hall JE, Barney JA, Uhrich TD, Colinco MD.  The Effects of Increasing Plasma Concentrations of Dexmedetomidine in Humans.  Anesthesiology.  2000;93:382-94
  8. Jakob SM, Ruokonen E, Grounds RM et al. Dexmedetomidine vs Midazolam or Propofol for Sedation During Prolonged Mechanical Ventilation: Two Randomized Controlled Trials.  JAMA. 2012;307(11):1151-60
  9. MacLearen R, Preslaski CR, et al.  A randomized, double-blind pilot study of edexmedetomidine versus midazolam for intensive care unit  sedation. J Intensive Care Med 2015; 30:167-175.
  10. Shehabi Y, Grant P, Wolfenden H, Hammond N et al.  Prevalence of Delirium with Dexmedetomidine Compared with Morphine Based Therapy after Cardiac Surgery.  Anesthesiology.  2009;111:1075-84
  11. Tan JA, Ho KM.  Use of dexmedetomidine as a sedative and analgesic agent in critically ill adult patients: a meta-analysis.  Intensive Care Med. 2010;36:926-39
  12. Riker RR, Shehabi Y, Bokesch PM et al.  Dexmedetomidine vs Midazolam for Sedation of Critically Ill Patients: A Randomized Trial.  JAMA.  2009;301(5):489-99
  13. Pandharipande PP, Pun BT, Herr DL et al.  Effect of Sedation with Dexmedetomidine vs Lorazepam on Acute Brain Dysfunction in Mechanically Ventilated Patients: The MENDS Randomized Controlled Trial.  JAMA.  2007;298(22):2644-53
  14. Hilliard N, Brown S, Mitchinson S. A case report of dexmetetomidine used to treat intractable pain and delirium in a tertiary palliative care unit. Pall Med 2015; 29:278-281.
  15. Soares LG, Naylor C, Martins MA, Peixoto G.  Letter: Dexmedetomidine: A New Option for Intractable Distress in the Dying.  J Pain Symptom Manage.  2002;24(1):6-8
  16. Hillard NK, Brown SB. Pilot Study Comparing Treatment With Dexmedetomidine to Midazolam for Symptom Control in Advanced Cancer Patients. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2013 Jul 9]. Available from: http://clinicaltrials.gov/ct2/show/NCT01687751?term=dexmedetomidine+palliative&rank=1.  NLM Identifier: NCT01687751.
  17. Buck ML.  Dexmedetomidine for Sedation in the Pediatric Intensive Care Setting. Pediatr Pharm. 2006;12(1).  http://www.medscape.com/viewarticle/524752_9.  Accessed July 28, 2013. 
  18. Friedberg BL.  Propofol in Office-Based Plastic Surgery. Semin Plast Surg.  2007:21(2): 129-32.

Authors’ Affiliations: University of Maryland, Baltimore, MD (KW); Duquense University, Pittsburgh, PA (KM); University of Minnesota Medical School and Fairview Health Services, Minneapolis, MN (DAR).  

Conflict of Interest Disclosure: The authors have disclosed no relevant conflicts of interest.

Version History:  First published May 2014. Re-copy-edited in September 2015 by Sean Marks MD to reflect changes in FDA indications, references # 9 and 14 were also added and incorporated into the text.