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Three Part Question

For [patients with acute sickle cell pain crisis], does [ketamine as an adjuvant to standard opioid therapy] [reduce the amount of opioids used]?

Clinical Scenario

A 24 year old male presents to the ED in an acute sickle cell pain crisis. He is requiring increasing amounts of opioids to control his pain with little effect. You wonder if a subdissociative dose of ketamine may be effective to control his pain and reduce his overall opioid consumption.

Search Strategy

Ovid MEDLINE(R) ALL 1946 to January 30, 2020

[exp Anemia, Sickle Cell/ or sickle cell.mp.] AND [ketamine.mp. or exp Ketamine/]

Search Outcome

21 papers found of which the following were excluded: 9 irrelevant, 2 study protocols with no data, 4 case studies/series, and 3 review papers. A total of 3 papers were included.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Neri CM, Pestieau SR, Young H, Elmi A, Finkel JC, et al. 2014 USA	Children and adolescents	Retrospective case-crossover study	Mean total daily opioid dose (morphine equivalents) with ketamine + opioid patient controlled analgesia (PCA) vs opioid PCA only	Ketamine + opioid PCA: 0.04 mg/kg/hr vs Opioid PCA only: 0.032 mg/kg/hr (p=0.0038)	Non-randomized design results in potentially skewed case selection of those who received ketamine. Small number of participants.
Nobrega, Sheehy, Lippold, Rice, Finkel, Quezado 2017 USA	Children and adolescents	Retrospective cohort study	Change in opioid consumption (morphine equivalents) from before starting ketamine infusion to the day after ketamine infusion discontinuation	Mean baseline opioid consumption: 3.36 mg/kg/day vs After ketamine discontinuation mean opioid consumption: 2.06 mg/kg/hr Change mean = -1.30 mg (p < 0.001)	Retrospective cohort study results in non-uniform treatment regimens. No control arm.
Puri, Morgan, Anghelescu 2019 USA	Children and adolescents	Retrospective case-crossover study	Total opioid consumption (morphine equivalents) with ketamine + opioid PCA vs opioid PCA only	Patient 1: Opioid PCA only = 0.48 mg/kg/day vs Ketamine + opioid PCA = 0.38–0.44 mg/kg/day Patient 3: Opioid PCA only = 0.73 mg/kg/day vs Ketamine + opioid PCA = 0.60 mg/kg/day Patient 4: Opioid PCA only = 0.34 mg/kg/day vs Ketamine + opioid PCA = 0.56 mg/kg/day	Some patients received both ketamine and lidocaine. No standardized dosing of ketamine. Didn't calculate p-values. Small number of patients.

Comment(s)

While there are several case reports and series published on this topic, only a few cohort studies with case controls demonstrate promising results. No randomized control trials have yet to be published looking at the use of ketamine as an adjunct to standard opioid therapy. In addition, the majority of studies appear to only involve children and adolescents.

Clinical Bottom Line

More evidence is needed to support the use of ketamine as an adjunct to standard opioid therapy.

References

1. Neri CM, Pestieau SR, Young H, Elmi A, Finkel JC, et al. Low-dose Ketamine for Children and Adolescents with Acute Sickle Cell Disease Related Pain: A Single Center Experience. Journal of Anesthesia and Clinical Research 2014; 1-5
2. Raissa Nobrega, Kathy A. Sheehy, Caroline Lippold, Amy L. Rice, Julia C. Finkel and Zenaide M.N. Quezado Patient characteristics affect the response to ketamine and opioids during the treatment of vaso-occlusive episode-related pain in sickle cell disease Pediatric Research 2017; 445-454
3. Latika Puri, Kyle J. Morgan, and Doralina L. Anghelescu Ketamine and lidocaine infusions decrease opioid consumption during vaso-occlusive crisis in adolescents with sickle cell disease Current opinion in supportive and palliative care 2019; 402-407