What evidence supports the use of ketamine in pain management of vaso-occlusive episodes in patients with sickle cell disease?

Introduction
Sickle cell disease (SCD) is a group of inherited blood disorders characterized by atypical hemoglobin that has a sickle shape (HbS).1 Unlike normal biconcave red blood cells (RBCs), sickle-shaped RBCs undergo an abnormal polymerization under conditions of low oxygen; this can lead to impaired circulation, destruction of RBCs, and inflammatory responses. As a recessive disorder, the pattern of inheritance may be heterozygous (termed sickle cell trait) that maintains one normal β-globin–producing gene; these heterozygous individuals are typically asymptomatic. Those with homozygous disease (HbSS) are often referred to as having sickle cell anemia (SCA), which has more frequent and severe clinical manifestations. Sickle cell disease predominantly affects people of Sub-Saharan African descent, with approximately 100,000 individuals affected in the US, representing roughly 1 of every 365 Black or African-American births.2 Annually, over 230,000 hospitalizations in the US are attributed to SCD, representing a significant economic impact of approximately $2.4 billion.3

Painful vaso-occlusive episodes (VOEs), previously known as sickle cell crises, are a characteristic presentation of SCD and contribute to the burden of illness.4 These VOEs occur when sickled RBCs obstruct the microcirculation and adhere to the vascular endothelium, leading to tissue ischemia and inflammation.3 Pain associated with VOEs typically affects the lower back, joints, and extremities, and is described as sudden, throbbing, and sharp in nature. These VOEs cause approximately 95% of SCD-related hospitalizations, and have a significant negative impact on quality of life, potentially exceeding that of SCD-related organ damage.3

Management of VOEs typically includes parenteral opioids and non-steroidal anti-inflammatory drugs (NSAIDs).1,3-5 However, management is challenging because of risks associated with opioid therapy and the limited evidence regarding adjunctive therapies such as supplemental oxygen and fluid therapy.3 For this reason, management is typically dictated by patient-reported pain and is highly individualized. Moreover, opioids may adversely influence the RBC membrane structure and promote inflammation, further contributing to vaso-occlusion. Lastly, negative attitudes of healthcare providers, such as believing that patients with SCD exaggerate their pain, can lead to overly conservative pain management.6

The potential role of ketamine in management of VOEs is gaining greater recognition.7,8 An NMDA receptor antagonist traditionally used as a general anesthetic, ketamine can interrupt the transmission of pain signals in the central nervous system, providing analgesia without some of the hallmark risks of opioids. This unique mechanism may offer particular benefit in patients who are refractory or intolerant to opioids, and may reduce their consumption and adverse effects. Although ketamine carries risk of adverse dissociative and hemodynamic effects, administration at sub-anesthetic doses (defined by some as <1 mg/kg/hour) may balance safety and efficacy.8 Because questions may arise regarding the emerging literature on this topic, this review describes current evidence for use of ketamine in management of VOEs of SCD, with a focus on interventional studies.

Supporting literature
A number of case reports and case series have been published describing use of ketamine for treatment of VOEs of SCD.7,8 These date from the first reported successful use of ketamine in this setting in a series of 5 children and adolescents hospitalized for acute VOEs.9 Case reports and series continue to be published that indicate the potential benefit of ketamine in this setting.10-12 While these publications have contributed meaningfully to the literature, they constitute a body of evidence of lower methodologic quality compared with more recent reports. Therefore, the literature summary in this review will focus on higher-quality randomized controlled trials (RCTs).

Randomized controlled trials
To date, the studies of highest methodologic quality evaluating ketamine in patients with VOEs of SCD include two RCTs.13,14 The first of these was a double-blind noninferiority trial by Lubega and colleagues.13 This trial evaluated the noninferiority of ketamine 1 mg/kg intravenous (IV) infusion compared with morphine 0.1 mg/kg IV infusion in 240 pediatric patients with severe SCD-associated pain presenting to a hospital in Uganda. Ketamine doses were diluted to 15 mL with normal saline in syringes and infused IV over 10 minutes. Ketamine was determined to be noninferior to morphine for the primary endpoint of maximum change in Numeric Pain Rating Scale ([NPRS], percentage change, 66.4% vs. 61.3%; mean difference, 5.5%; 95% confidence interval [CI], -2.2 to -13.2). The greatest decrease in NPRS was achieved earlier with ketamine than with morphine (19.8 vs 34.1 minutes). However, the duration of effect was shorter with ketamine; at 2 hours, a greater percentage of patients treated with morphine were still experiencing maximum pain relief (45.8% vs. 37.5%; risk ratio, 1.2; 95% CI, 0.9 to 1.7). Fewer patients treated with ketamine experienced treatment failure (28.3% vs 40%; p=0.07). Patients treated with ketamine experienced more frequent adverse effects (37.5% vs. 3.3%); however, these were transient, predictable, and non-severe (eg, dysphoria, hypersalivation).

The other RCT by Alshahrani and colleagues was a double-blind, pragmatic trial in which 278 adults with VOE presenting to an emergency department (ED) in Saudi Arabia were randomized to a single infusion of either ketamine 0.3 mg/kg or morphine 0.1 mg/kg.14 Ketamine doses were diluted in 100 mL of normal saline and infused IV over 30 minutes. In addition, treating physicians were permitted to prescribe their choice of either IV acetaminophen, IV lornoxicam, or intramuscular diclofenac. At 2 hours, mean NPRS in patients treated with ketamine or morphine were not significantly different (5.7 or 5.6, respectively; p=0.63). However, after the initial intervention, cumulative doses of morphine were lower in patients treated with ketamine (0.07 vs 0.13 mg/kg, respectively; p<0.001). Frequency of hospital admission did not differ between patients treated with ketamine vs morphine (20.3% vs 24.6%; p=0.4). Patients treated with ketamine experienced 9 of the 12 total reported adverse events, although these were transient and non-severe (dizziness, nausea, vomiting).

Systematic reviews of observational research
While the RCTs by Lubega and Alshahrani offer the highest-quality evidence on ketamine use in VOEs of SCD, observational research offers important insight and bears mention. Several systematic reviews have characterized the observational research evaluating ketamine in this setting.7,8 The most recent of these is a 2021 systematic review by Harris and colleagues, which reviewed literature published up to 2020.8 The authors identified 7 case reports and case series, 1 prospective uncontrolled study, 6 retrospective studies, 3 cohort studies, and the RCT by Lubega et al described above. Like the RCTs, observational studies have reported a generally consistent pattern of improvement in pain and/or opioid consumption, with adverse events that are typically transient (eg, nystagmus, hypotension, dysphoria, dissociative symptoms) and rarely severe (eg, respiratory depression).7,8  Consistent with the prescribing information, these reviews identified adverse events suggesting that ketamine should be avoided in patients with a history of seizure, stroke, increased intracranial pressure, psychosis, altered mental status, and labile hypertension.8,15

Notably, authors of systematic reviews highlight the significant variability with regard to dosing, timing of initiation, duration of infusion, and timing of discontinuation of ketamine.7,8 Reported ranges for dosage and administration parameters include starting dosages from 0.025 to 0.4 mg/kg/hour, maximum dosages from 0.15 to 1 mg/kg/hour, timing of initiation from presentation to the ED to days after admission, and timing of discontinuation from after several doses to after discharge at day 7 utilizing an oral ketamine regimen. This heterogeneity indicates the need for more rigorous evaluations to support more standardized dosing protocols.

Recommendations and Uncertainties
Findings from studies summarized above are promising, but are limited by their heterogeneity. This is evident in recommendations on use of ketamine in the 2020 guideline for management of acute and chronic pain in SCD by the American Society of Hematology (ASH).5 The guideline recommends that for hospitalized adults and children presenting with acute pain related to SCD, a subanesthetic (analgesic) ketamine infusion may be used as adjunctive treatment of pain that is refractory or not effectively treated with opioids alone. Reflecting the limited and heterogeneous evidence described above, this recommendation is conditional and based on very low certainty evidence. The ASH guideline recommends a starting ketamine dose of 0.1 to 0.3 mg/kg/hour, and a maximum dose of 1 mg/kg/hour. While the guideline panelists identified that the benefits of ketamine in this setting generally outweigh the risks, they note that an experienced practitioner should administer the drug. Notably, the review of evidence for the ASH guideline included only the RCT by Lubega et al. It is unclear how the more recently published RCT by Alshahrani and colleagues may impact future recommendations, given its differences in population, intervention, and setting.

Also unknown are the effects of repeated use of ketamine in treatment of VOEs of SCD and long-term use.7,8 Currently, the body of evidence has only characterized short-term use. Frequent or repetitive ketamine use may be associated with cognitive impairment. Because Harris and colleagues identified heterogeneity in effects (greater analgesia in males compared with females, and in patients with HbSS genotype), it is feasible that these or other characteristics may predict treatment response.8

Additionally, few studies have evaluated ketamine administered by non-parenteral routes.7,8 This question is relevant because off-label administration of ketamine by intranasal and oral routes has been reported in other indications such as mood disorders.16 Among the literature in SCD, only one study evaluated oral administration of ketamine in a single adult patient at a dose of 15 mg every 6 hours to a maximum of 50 mg every 6 hours.8,17 While an RCT of intranasal ketamine administration has been registered, results are not yet available.18 Clinicians should be aware of this dearth of experience regarding use of ketamine by non-parenteral routes in VOEs of SCD.

Conclusion
The evidence supporting use of sub-anesthetic doses of ketamine in management of VOEs in patients with SCD continues to expand. Although the majority of these publications are case studies and case series reporting successful use, two RCTs have demonstrated that ketamine infusions are similar in efficacy to standard-of-care treatment with parenteral opioids, and may decrease opioid consumption. Currently, guidelines from ASH conditionally recommend ketamine infusion as adjunctive treatment of pain that is not responsive to opioids alone, and that the drug should be administered by experienced practitioners because of its safety risks. However, this recommendation is based on very low certainty evidence, which is limited by heterogeneity in dosage and administration. Further research will continue to elucidate the safety and efficacy of ketamine used in VOEs of SCD, which may help establish a more well-defined dosing regimen.

References

  1. Han J, Saraf SL, Gordeuk VR. Sickle Cell Disease. In: DiPiro JT, Yee GC, Haines ST, Nolin TD, Ellingrod VL, Posey LM, eds. DiPiro’s Pharmacotherapy: A Pathophysiologic Approach. 12th ed. McGraw Hill; 2023. accesspharmacy.mhmedical.com/content.aspx?aid=1197560330
  2. Centers for Disease Control and Prevention. Data & Statistics on Sickle Cell Disease. Centers for Disease Control and Prevention. Updated May 2, 2022. Accessed June 5, 2023. https://www.cdc.gov/ncbddd/sicklecell/data.html
  3. Darbari DS, Sheehan VA, Ballas SK. The vaso-occlusive pain crisis in sickle cell disease: Definition, pathophysiology, and management. Eur J Haematol. 2020;105(3):237-246. doi:10.1111/ejh.13430
  4. Kavanagh PL, Fasipe TA, Wun T. Sickle Cell Disease: A Review. JAMA. 2022;328:57-68. doi:10.1001/jama.2022.10233
  5. Brandow AM, Carroll CP, Creary S, et al. American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain. Blood Adv. 2020;4:2656-2701. doi:10.1182/bloodadvances.2020001851
  6. Glassberg JA. Improving Emergency Department-Based Care of Sickle Cell Pain. Hematology. 2017;2017(1):412-417. doi:10.1182/asheducation-2017.1.412
  7. Alshahrani MS, Alghamdi MA. Ketamine for Sickle Cell Vaso-Occlusive Crises: A Systematic Review. Saudi J Med Med Sci. 2021;9(1):3-9. doi:10.4103/sjmms.sjmms_218_20
  8. Harris EM, Vilk E, Heeney MM, Solodiuk J, Greco C, Archer NM. A systematic review of ketamine for the management of vaso-occlusive pain in sickle cell disease. Pediatr Blood Cancer. 2021;68(7):e28989. doi:10.1002/pbc.28989
  9. Zempsky WT, Loiselle KA, Corsi JM, Hagstrom JN. Use of low-dose ketamine infusion for pediatric patients with sickle cell disease-related pain: a case series. Clin J Pain. 2010;26(2):163-167. doi:10.1097/AJP.0b013e3181b511ab
  10. Yu H, Chen A, Chen E, Long LS, Agrawal AK. Low-dose Ketamine Infusion for Pediatric Hematology/Oncology Patients: Case Series and Literature Review. J Pediatr Hematol Oncol. 2022;44(1):e188-e193. doi:10.1097/mph.0000000000002290
  11. Martinez MR, Garmon EH, Starling GD, Sheth MA. Ketamine as an Analgesic Adjunct for Opioid-Induced Hyperalgesia in a Patient With a Sickle Cell Pain Episode. Ochsner J. 2022;22(3):281-284. doi:10.31486/toj.22.0011
  12. Froomkin J, Knoebel RW, Dickerson D, Soni H, Szwak J. Impact of Ketamine in the Management of Painful Sickle Cell Disease Vaso-Occlusive Crisis. Hosp Pharm. 2022;57(1):176-181. doi:10.1177/0018578721999806
  13. Lubega FA, DeSilva MS, Munube D, et al. Low dose ketamine versus morphine for acute severe vaso occlusive pain in children: a randomized controlled trial. Scand J Pain. 2018;18(1):19-27. doi:10.1515/sjpain-2017-0140
  14. Alshahrani MS, AlSulaibikh AH, ElTahan MR, et al. Ketamine administration for acute painful sickle cell crisis: A randomized controlled trial. Acad Emerg Med. 2022;29(2):150-158. doi:10.1111/acem.14382
  15. Ketamine hydrochloride. Package insert. Hospira; 2022.
  16. McIntyre RS, Carvalho IP, Lui LMW, et al. The effect of intravenous, intranasal, and oral ketamine in mood disorders: A meta-analysis. J Affect Disord. 2020;276:576-584. doi:10.1016/j.jad.2020.06.050
  17. Jennings CA, Bobb BT, Noreika DM, Coyne PJ. Oral ketamine for sickle cell crisis pain refractory to opioids. J Pain Palliat Care Pharmacother. 2013;27(2):150-154. doi:10.3109/15360288.2013.788599
  18. Young JR, Sawe HR, Mfinanga JA, et al. Subdissociative intranasal ketamine plus standard pain therapy versus standard pain therapy in the treatment of paediatric sickle cell disease vaso-occlusive crises in resource-limited settings: study protocol for a randomised controlled trial. BMJ Open. 2017;7(7):e017190. doi:10.1136/bmjopen-2017-017190

Prepared by:
Ryan Rodriguez, PharmD, MS, BCPS
Clinical Associate Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

July 2023

The information presented is current as June 4, 2023. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.