Abstract
The aim of the study is to determine if ketamine infusions in combination with opioid therapy for the management of sickle cell disease (SCD) presenting with vaso-occlusive crisis (VOC) resulted in a length-of-stay difference compared to when ketamine was not utilized. This single center, retrospective, observational study performed at an academic medical center evaluated 12 adult patients with SCD-VOC who received a ketamine infusion with standard opioid therapy between 2014 and 2017. Patients were excluded if the primary diagnosis was not VOC or they did not survive to discharge. Additionally, safety and oral morphine equivalents at various time points were compared. Patients were used as their own control using the previous SCD-VOC hospitalization to evaluate the relative impact of ketamine. Wilcoxon signed-rank and rank sum were used in statistical analysis. When comparing opioid doses during the ketamine infusion, a P-value <.005 was considered statistically significant to account for multiple comparisons. The median length-of stay when ketamine was employed was similar to the previous admission with only opioid therapy (12 vs 12 days, P = .317). The median opioid dose 24 hours prior to starting ketamine was greater than during the first 24 hours of ketamine use (1278 vs 1020 mg, P = .022) and 24 hours after stopping ketamine (1278 vs 1035 mg, P = .014); however, this was not statistically significant. During 5 ketamine infusions, patients experienced side effects; however, only 1 necessitated transfer to the intensive care unit. Compared to standard opioid therapy, ketamine infusions were generally well tolerated and may be effective at reducing opioid use during SCD-VOC but did not decrease hospital length-of-stay.
Keywords: analgesics, intravenous therapy, pain management
Introduction
Painful vaso-occlusive crises (VOC) are the hallmark symptom associated with adult sickle cell disease (SCD) and can be frequent, chronic, and debilitating and are often refractory to standard treatment. 1 Opioids are the mainstay of treatment for acute pain crises. 1 Daily pain is reported by 29% of patients, and most patients report pain on more than 50% of days. 2 By adulthood, most patients have over 15 years of intermittent opioid exposure. 3 The PiSCES Project reported that opioids are used in over 75% of home pain days, and almost 40% of patients were managed with long-acting opioids. 4
The recommendations for management of acute pain with VOC have remained largely unchanged since the American Pain Society’s 1999 guidelines. Recent updates from the 2014 National Institute of Health’s guidelines recommend rapidly initiating parenteral opioids. 1 In order to overcome tolerance from home opioid therapy, prescribers can select to use higher doses or alternative agents to address the VOC pain. If a patient requires admission, around-the-clock dosing of opioids is recommended using scheduled bolus doses or intravenous patient-controlled analgesia (IV-PCA). Doses should be titrated to reach patient reported satisfaction with pain relief. 1 Such an approach results in challenges for clinicians as escalating opioid doses can lead to toxicity, and in some cases fail to relieve pain.
Chronic pain or undertreated acute pain may induce maladaptive changes in the central and peripheral nervous system. This central sensitization predisposes patients to augmented pain signal processing and opioid induced hyperalgesia (OIH). 5 The glutamatergic NMDA-receptors in the spinal cord are upregulated in the setting of chronic pain and have been implicated as a driver in the development of OIH. This results in down-regulation of the mu-opioid receptor, and thus refractoriness to traditional mu-opioid agonists. 6 NMDA receptor agonism is pronociceptive resulting in hyperexcitability. Ketamine is a potent NMDA-receptor antagonist that attenuates the central nervous system’s processing of nociceptive afferents. 7 Subanesthetic doses of ketamine can help to reduce the central sensitization and recouple the effects of opioids in the spinal cord to reduce opioid exposure and improve analgesic effects.8-10 Ketamine has demonstrated positive effects in opioid resistant or refractory cancer pain syndromes, surgical pain management as an adjuvant to opioids, and is increasingly used in the treatment of chronic neuropathic and non-cancer pain.11-13 New guidelines from the American Society of Hematology recommend the use of subanesthetic doses of ketamine as an adjunctive therapy in refractory pain in SCD. Although the data is limited, the recommended dose of ketamine is 0.1 to 0.3 mg/kg/hour with a maximum of 1 mg/kg/hour; however, this is a conditional recommendation as there has been limited experience utilizing ketamine infusion for the management of SCD-VOC pain. 14
In 2014, our institution implemented a low-dose continuous-infusion ketamine protocol that allowed, under the direction of the acute pain service, administration for management of acute pain syndromes, including SCD-VOC refractory to standard opioid analgesics, in non-intensive care unit patients.
The purpose of this study is to evaluate whether the use of ketamine infusions in addition to opioid therapy will impact the length of stay. With limited information available, this study will describe our experience and contribute to the body of literature available regarding efficacy and safety of ketamine in adults with SCD with VOC pain.
Methods
This single-center, retrospective, observational study was conducted at an academic medical center located on the south-side of Chicago from January 1, 2014 through June 30, 2017. The study was approved by the medical center’s Institutional Review Board. The electronic medical record was utilized to identify the study population of adult patients 18 years of age and older admitted to the adult hospital that had a diagnosis of VOC as well as a diagnosis of SCD and received a ketamine infusion to help manage their pain.
At our institution, all patients with VOC receive opioid therapy at the discretion of the provider including prior-to-admission long-acting oral opioids, IV-PCA, and non-opioid analgesics. Providers often reference previous PCA settings to determine dose and lockout intervals and are able to adjust these as deemed appropriate based on pain scores and clinical judgment. For patients without sufficient relief of pain from IV-PCA in conjunction with long-acting opioids and non-opioid analgesics, a consult to the acute pain service can be placed for assistance with management of refractory pain. The acute pain service is able to recommend the use of low-dose ketamine infusion (1-5 µg/kg/min) for patients with opioid tolerance, severe neuropathic pain including central sensitization, or evidence of opioid induced hyperalgesia. Opioid escalation is not recommended during ketamine titration due to the risk of sedation and respiratory depression.
The primary endpoint of this study was to determine if ketamine infusions when used in combination with opioid therapy for the management of patients with SCD presenting with VOC pain resulted in a length-of-stay difference compared to when ketamine was not utilized. Patients were used as their own control using the previous SCD-VOC hospitalization to evaluate the relative impact of ketamine on hospital length-of-stay. If a patient had multiple admissions in which ketamine was used, the first ketamine infusion admission was used to eliminate the potential concern for selection bias. Secondary endpoints include: change in opioid dose from admission to discharge, time between admissions, total opioid use, incidence of naloxone administration, and incidence of psychosis and central nervous system effects or intensive care unit transfer. Change in opioid dose from admission to discharge and time between admissions is reported for the first administration of ketamine only. All other secondary endpoints include data from all admissions where ketamine was administered. Opioid doses were converted to oral morphine equivalents and were used to evaluate discharge opioid prescriptions and inpatient opioid consumption. 15 Home opioid doses were calculated using long-acting opioid doses plus the maximum allowable short-acting opioid doses. For example, if the patient was receiving oxycodone controlled-release 60 mg every 12 hours and oxycodone immediate release 15 mg every 4 hours as needed for pain, the patient could have received a maximum of 210 mg of oxycodone in a 24 hour period, equivalent to 315 mg of oral morphine equivalents.
The statistical analysis was performed using StataCorp. 2013 (College Station, TX: StataCorp LP). Descriptive statistics were summarized using median and interquartile range. Comparisons of opioid consumption over time categories were analyzed using the Wilcoxon signed-rank test with Bonferroni correction for multiple comparisons. An adjusted P-value of .005 was considered statistically significant in comparisons of opioid dosing before, during, and after the ketamine infusion. The Shapiro-Wilk test was used to test the ANOVA assumption of normally distributed errors, and the Levene’s F test was used to test the assumption of homogeneity of variance. Wilcoxon signed-rank and Wilcoxon rank sum tests were used to analyze paired and unpaired nonparametric data, respectively.
Results
A total of 43 patient encounters were screened for eligibility between January 2014 and June 2017, of which 19 were excluded. Reasons for exclusion included a primary diagnosis other than VOC (11), admission to the children’s hospital (4), death during admission (2), ketamine not administered (1), and other (1). Twenty-four (56%) encounters met inclusion criteria, accounting for 12 unique patients. One patient accounted for 3 of the included admissions, 1 patient accounted for 5 of the included admissions, and 1 patient accounted for 7 of the included admissions. All other patients had 1 admission where ketamine was administered. The median day of the start of the ketamine infusion was 3 days (IQR 2-5.5). The median starting dose of ketamine in this study was 3 µg/kg/min (range of 2-5 µg/kg/min) with an average duration of 64 hours (range 5-138 hours). The ketamine dose was increased in 7 of the 24 admissions. Baseline characteristics and analgesic dosing are summarized in Tables 1 and 2.
Table 1.
Baseline Characteristics of 12 Patients Receiving Ketamine for VOC.
Baseline characteristics | |
---|---|
Age, median years (IQR) | 28 (26.8-30.2) |
Female sex, n (%) | 10 (83) |
African American, n (%) | 12 (100) |
Patients following with institution’s hematology clinic, n (%) | 7 (58) |
Patients following with institution’s pain clinic, n (%) | 2 (17) |
Prescribed long-acting opioids prior to admission, n (%) | 9 (75) |
Table 2.
Opioid and Ketamine Usage in 24 Admissions When Ketamine Was Used for VOC.
Opioid and ketamine usage | |
---|---|
Home opioid dose (mg oral morphine equivalents), median (IQR) | 761 (443-1020) |
Hospital day of ketamine start, median (IQR) | 3 (2-5.5) |
Ketamine duration (h), median (IQR) | 64 (38-90) |
The primary endpoint comparing the median hospital length-of-stay during the first hospitalization ketamine was employed was similar to the previous SCD-VOC admission of standard opioid therapy (12 vs 12 days, P = .317) as depicted in Figure 1. Patients required a lower total daily opioid dose during and following the ketamine infusion when compared to the 24 hours prior to administering ketamine; however, this was not statistically significant (Figure 2). The prior to admission opioid dose versus discharge opioid dose during the first ketamine encounter did not differ significantly (Figure 3). The median time to the next admission for VOC was longer after receipt of ketamine when compared to the prior encounter without ketamine; however, this did not reach statistical significance (59 vs 22 days, P = .38).
Figure 1.
Hospital length of stay (in days) comparing hospitalizations when ketamine was utilized versus previous hospitalizations when ketamine was not used (n = 24, 12 vs 12 days, P = .317). Box and whisker plot where the box represents the upper and lower quartile with the median represented as a line within the box. The whiskers represent 1.5 times the IQR which is then added to Q3 (upper whisker) and subtracted from Q1 (lower whisker).
Figure 2.
Box and whisker plot showing: (A) the change in opioid dose the 24 hours before (1278 mg), (B) the first 24 hours of ketamine infusion (1020 mg), (C) 24 to 48 hours of ketamine infusion (1055 mg), (D) 48 to 72 hours of ketamine infusion (1045 mg), and (E) 24 hours after the ketamine infusion (1035 mg). No statistically significant differences were found between opioid doses prior to starting ketamine and any subsequent time period (n = 24, P = .0223, .0191, .1128, and .0146, respectively). All values that fall outside of the whisker are considered outlier values represented as dots.
Figure 3.
Median prior to admission versus discharge opioid doses for index ketamine admission in mg of morphine equivalents (n = 12, 694.5 vs 523 mg, P = .436).
Safety
In terms of safety, no patients receiving ketamine required the administration of naloxone, a total of 5 infusions had a documented CNS adverse event, and 1 patient required transfer to the intensive care unit for exchange transfusion (Table 3). Of these, 2 were reported as somnolence, 1 experienced altered mental status, 1 experienced a “feeling of dissociation,” and 1 patient reported hallucinations. The patient that experienced a feeling of dissociation and the patient who experienced hallucinations both requested ketamine to be discontinued. Ketamine was discontinued by the primary service in the patient that experienced altered mental status, as well as both patients that experienced somnolence. In 1 patient that experienced somnolence, the ketamine dose was titrated down first, and then discontinued when this did not result in decreased somnolence. This patient also began gabapentin at the same time as ketamine, which may have contributed to increased somnolence. The other patient that experienced somnolence was noted as having been somnolent due to beginning methadone treatment the day prior to ketamine initiation. It is unclear from documentation if the addition of ketamine worsened this effect or not. During the included admissions, 2 patients were diagnosed with acute chest syndrome, 1 of which was admitted to the intensive care unit for exchange transfusion, which began after the patient received ketamine infusion. All of the adverse events noted happened on initial infusion of ketamine and none on subsequent infusions. None of the patients in the study that had adverse events were re-challenged with ketamine during the study period.
Table 3.
Secondary Outcomes of 24 Admissions with Ketamine Use.
Outcome | |
---|---|
Time to ketamine start from admission | |
Index ketamine admission, median day (IQR) (n = 12) | 3 (1.75-5.75) |
Subsequent ketamine admissions, median day (IQR) (n = 12) | 3 (2-5.25) |
Incidence of naloxone administration, n (%) | 0 (0) |
Incidence of acute chest syndrome, n (%) | 2 (8) |
Incidence of ICU transfer, n (%) | 1 (4) |
Incidence of CNS adverse event, n (%) | 5 (21) |
Discussion
To our knowledge, this is the largest study evaluating ketamine use in VOC to date. We report the use of a low-dose ketamine infusion in 24 VOC-related admissions in 12 patients with sickle cell disease. The use of ketamine in management of VOC has been described in case reports of 16 experiences. Patients received a range of durations and doses. In those case reports, responders reported a rapid reduction in pain, and those with higher opioid doses seem to respond better.16-19
A difference in length of stay was not seen in this analysis, though this may have been due to the small sample size. We chose to use patients as their own controls as there is much variability in the course of VOC for different patients, evidenced by the widely varying length of stay seen in this study (range 5-25 days). LOS also varied widely in other case reports and case series in this patient population (range 10-38 days).17,20
The results of this study also revealed similar findings to previously published case reports that inpatient opioid usage may be decreased when combined with low-dose ketamine infusions for VOC in adult patients with SCD.16,19,21 Though reduction in opioid doses did not reach statistical significance possibly due to sample size, we found that when compared to the median opioid dose prior to starting ketamine, average opioid use was numerically decreased by 20% in the 24 hours after starting ketamine and by 19% in the 24 hours after ketamine was discontinued. Median opioid doses were numerically reduced by over 50% and 25% in 7 (29%) and 12 (50%) admissions after ketamine infusion. This reduction in opioid usage supports the mechanism and proposed benefits of ketamine in its ability to recouple the effects of opioids in the nervous system and act as an opioid sparing therapy in patients not previously responsive to opioids.
We observed that opioid doses at discharge were 25% lower than doses patients had been prescribed prior to admission; although, this was not statistically significant. Patients often still have residual pain at the time they are discharged from the hospital, and they may require higher doses of pain medications immediately after being discharged than normal. Guidelines recommend writing prescriptions for equianalgesic doses of oral pain medications as patients were receiving in the hospital, regardless of previous home doses. 22 Based on this, even a small reduction in opioid doses at discharge could be a more clinically significant finding.
Our approved institution-specific low-dose ketamine infusion protocol uses dosing range from 1 to 5 µg/kg/min based on ideal body weight. Seven patients had ketamine infusions increased after 24 hours, and no patients received more than 1 dose escalation. Previously published case reports used a wide variety of doses and durations of ketamine infusions from 1 to 4.2 µg/kg/min for 3 to 7 days, which is consistent with the dosing we observed.16,19,23 Many of these case reports and case series were in pediatric patients. In a case report where a 31-year-old male was given ketamine for VOC, infusions of ketamine 150 to 400 µg/min was used in addition to 1 to 5 mg bolus doses when the infusion rate was increased. The patient’s weight was not included, so direct comparison to dosing in our patients is not possible. 17
We hypothesized that using ketamine in patients where opioids were no longer sufficient for analgesia may potentially increase the amount of time between VOC and increase the amount of time between hospital admissions for VOC. This hypothesis was derived from the extended duration of pain relief experienced by patients with complex regional pain syndrome receiving subanesthetic ketamine infusions. 24 Following the first ketamine course, over half of patients remained pain free for at least 3 months and 31% remained pain free for 6 months. 24 In our study, the time from previous admission for VOC versus the time to next admission for VOC showed a numerical difference of 36.5 days that did not translate to statistical significance possibly because of sample size limitations. This is also a difficult outcome to evaluate as VOC admissions may be related to worsening disease or triggers outside of pain control that could confound the results. There are also several hospital systems in the area, and we only included admissions to our institution.
Limitations of our study are the retrospective nature of data collection which may limit the completeness of data collection as well as limit the ability to control for confounders. For example, the patient controlled analgesia opioid doses relied on accurate charting of volumes of medication used by nurses, which is not always consistent. An additional confounder is that the study authors had no control over any concomitant analgesics or interventions that a patient was receiving. Secondly, pain scores were not assessed by this study. Pain intensity scores, especially in acute-on-chronic pain syndromes like SCD-VOC, are not sensitive markers of pain relief. This is a limitation at our organization as we do not have a reliable functional assessment scale that is consistently recorded in the electronic health record. Furthermore, the goal of analgesic therapy for SCD-VOC is not necessarily a lowering of the unidimensional pain score but rather a global improvement in functionality of which the VAS is used one component. Both of these represent an opportunity to improving the care of SCD-VOC and other acute-on-chronic pain conditions for measuring success of analgesia.25,26 The single-centered nature of the study may limit applicability of the results to other institutions and patient populations different than those seen at this institution. Also, though this is the largest study of its size in the adult SCD population, the number of patients remains relatively small, which may hinder the ability to show a difference in outcomes. Another limitation is that 3 patients had several encounters included in the analysis. The patient that accounted for 7 admissions was a high opioid utilizer and was kept on a stable home opioid regimen for 6 of these admissions (1020 mg morphine equivalents daily vs the average 703 mg daily) which may have affected outcomes; although we controlled for this by only considering the first ketamine admission when comparing home and discharge opioid doses.
Despite a lack of statistical differences seen in outcomes in patients at our institution, ketamine is still used by our acute pain service for the management of refractory VOC pain. For patients who experience pain relief with ketamine, administration on subsequent admissions or in the outpatient setting may be considered; however, patients who do not experience pain relief, other options are typically explored. Since the completion of this study, our institution has worked to build pathways in the electronic medical record that help providers determine when care should be escalated and acute pain service consulted to offer adjunctive measures. We believe this has likely lead to an increased awareness of alternative options and involvement of the acute pain service in management of refractory pain. We hope to see additional studies to support the use of ketamine in this patient population following the new guideline recommendations from the American Society of Hematology.
Conclusions
This analysis showed similar length of stay when a low-dose ketamine infusion when used for VOC pain in the adult SCD population. Although not significant, patients had lower opioid consumption during and after the ketamine infusion and were discharged on lower opioid doses than reported at admission. Ketamine infusions were generally well tolerated, with adverse CNS events occurring in 5 cases. Further studies need to be done with a larger population to determine if ketamine can reduce hospital length of stay, opioid consumption, and readmissions when used in addition to a standard pain regimen for VOC.
Footnotes
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iDs: Jennifer Froomkin
https://orcid.org/0000-0002-3851-4301
Randall W. Knoebel
https://orcid.org/0000-0002-0166-4955
References
- 1. Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of 2014 evidence-based report by expert panel members. JAMA. 2014;312(10):1033-1048. [DOI] [PubMed] [Google Scholar]
- 2. Smith WR, Penberthy LT, Bovbjerg VE, et al. Daily assessment of pain in adults with sickle cell disease. Ann Intern Med. 2008;148(2):94-101. [DOI] [PubMed] [Google Scholar]
- 3. Aisiku IP, Smith WR, McClish DK, et al. Comparisons of high versus low emergency department utilizers in sickle cell disease. Ann Emerg Med. 2009;53(5):587-593. [DOI] [PubMed] [Google Scholar]
- 4. Smith WR, McClish DK, Dahman BA, et al. Daily home opioid use in adults with sickle cell disease: the PiSCES project. J Opioid Manag. 2015;11(3):243-253. [DOI] [PubMed] [Google Scholar]
- 5. Koppert W, Sittl R, Scheuber K, Alsheimer M, Schmelz M, Schüttler J. Differential modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by S-ketamine and clonidine in humans. Anesthesiology. 2003;99(1):152-159. [DOI] [PubMed] [Google Scholar]
- 6. Lee M, Silverman S, Hansen H, Patel VB, Manchikanti L. A comprehensive review of opioid-induced hyperalgesia. Pain Physician. 2011;14(2):145-161. [PubMed] [Google Scholar]
- 7. Mion G, Villevieille T. Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings). CNS Neurosci Ther. 2013;19(6):370-380. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Shimoyama N, Shimoyama M, Inturrisi CE, Elliott KJ. Ketamine attenuated and reverses morphine tolerance in rodents. Anesthesiology. 1996;85(6):1357-1366. [DOI] [PubMed] [Google Scholar]
- 9. Ohnesorge H, Feng Z, Zitta K, Steinfath M, Albrecht M, Bein B. Influence of clonidine and ketamine on m-RNA expression in a model of opioid-induced hyperalgesia in mice. PLoS One. 2013;8(11):e79567. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Niesters M, Martini C, Dahan A. Ketamine for chronic pain: risks and benefits. Br J Clin Pharmacol. 2014;77(2):357-367. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Bredlau AL, Thakur R, Korones DN, Dworkin RH. Ketamine for pain in adults and children with cancer: a systematic review and synthesis of the literature. Pain Med. 2013;14(10):1505-1517. [DOI] [PubMed] [Google Scholar]
- 12. McNicol ED, Schumann R, Haroutounian S. A systematic review and meta-analysis of ketamine for the prevention of persistent post-surgical pain. Acta Anaesthesiol Scand. 2014; 58(10):1199-1213. [DOI] [PubMed] [Google Scholar]
- 13. Shteamer JW, Callaway MA, Patel P, Singh V. How effective is ketamine in the management of chronic neuropathic pain? Pain Manag. 2019;9(6):517-519. [DOI] [PubMed] [Google Scholar]
- 14. 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(12):2656-2701. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Remedy Health Media. Opioid conversion calculator. Accessed October 30, 2017. https://opioidcalculator.practicalpainmanagement.com/conversion.php
- 16. Meals CG, Mullican BD, Shaffer CM, Dangerfield PF, Ramierez RP. Ketamine infusion for sickle cell crisis pain in an adult. J Pain Symptom Manage. 2011;42(3):87-89. [DOI] [PubMed] [Google Scholar]
- 17. Uprety D, Baber A, Foy M. Ketamine infusion for sickle cell pain crisis refractory to opioids: a case report and review of literature. Ann Hematol. 2014;93(5):769-774. [DOI] [PubMed] [Google Scholar]
- 18. 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] [PubMed] [Google Scholar]
- 19. Tawfic QA, Faris AS, Kausalya R. The role of a low-dose ketamine-midazolam regimen in the management of severe painful crisis in patients with sickle cell disease. J Pain Symptom Manage. 2014;47(2):334-340. [DOI] [PubMed] [Google Scholar]
- 20. Hagedorn JM, Monico EC. Ketamine infusion for pain control in acute pediatric sickle cell painful crises. Pediatr Emerg Care. 2019;35(1):78-79. [DOI] [PubMed] [Google Scholar]
- 21. Palm N, Floroff C, Hassig TB, Boylan A, Kanter J. Low-dose ketamine infusion for adjunct management during vaso-occlusive episodes in adults with sickle cell disease: a case series. J Pain Palliat Care Pharmacother. 2018;32(1):20-26. [DOI] [PubMed] [Google Scholar]
- 22. U.S. Department of Health and Human Services. National Institutes of Health, National Heart, Lung, and Blood Institute. 2002. The management of sickle cell disease (NIH Publication No. 02-2117). Accessed October 30, 2017. https://www.nhlbi.nih.gov/files/docs/guidelines/sc_mngt.pdf
- 23. Neri CM, Pestieau SR, Darbari DS. Low-dose ketamine as a potential adjuvant therapy for painful vaso-occlusive crises in sickle cell disease. Paediatr Anaesth. 2013;23(8):684-689. [DOI] [PubMed] [Google Scholar]
- 24. Correll GE, Maleki J, Gracely EJ, Muir JJ, Harbut RE. Subanesthetic ketamine infusion therapy: a retrospective analysis of a novel therapeutic approach to complex regional pain syndrome. Pain Med. 2004;5(3):263-275. [DOI] [PubMed] [Google Scholar]
- 25. Dansie EJ, Turk DC. Assessment of patients with chronic pain. Br J Anaesth. 2013;111(1):19-25. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Levy N, Sturgess J, Mills P. “Pain as the fifth vital sign” and dependence on the “numerical pain scale” is being abandoned in the US: why? Br J Anaesth. 2018;120(3):435-438. [DOI] [PubMed] [Google Scholar]