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Intranasal Ketamine for Abortive Migraine Therapy in Pediatric Patients: A Single-Center Review
Journal Pre-proof Intranasal ketamine for abortive migraine therapy in pediatric patients: a single-center, retrospective review Adrian L. Turner, PharmD, Sabrina Shandley, PhD, PMP, Ean Miller, PharmD, BCPPS, M. Scott Perry, MD, Brian Ryals, MD PII:
S0887-8994(19)30924-5
DOI:
https://doi.org/10.1016/j.pediatrneurol.2019.10.007
Reference:
PNU 9680
To appear in:
Pediatric Neurology
Received Date: 4 June 2019 Revised Date:
16 October 2019
Accepted Date: 27 October 2019
Please cite this article as: Turner AL, Shandley S, Miller E, Perry MS, Ryals B, Intranasal ketamine for abortive migraine therapy in pediatric patients: a single-center, retrospective review, Pediatric Neurology (2019), doi: https://doi.org/10.1016/j.pediatrneurol.2019.10.007. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
Title: Intranasal ketamine for abortive migraine therapy in pediatric patients: a single-center, retrospective review Running Title: Intranasal ketamine for migraine
Authors: Adrian L. Turner, PharmDa†; Sabrina Shandley, PhD, PMPb; Ean Miller, PharmD, BCPPSa; M. Scott Perry, MDc; Brian Ryals, MDc
Corresponding Author: † [email protected]; 801 7th Avenue, Fort Worth, TX 76104, USA Affiliations 1 2 3 a
Department of Pharmacy, Cook Children’s Medical Center, Fort Worth, TX, USA
b
Research Administration Office, Cook Children’s Medical Center, Fort Worth, TX, USA
c
Jane and John Justin Neurosciences Center, Cook Children’s Medical Center, Fort Worth, TX,
USA
Manuscript Word Count: 3760 Table and Figure Count: 3 tables; 4 figures
1
Abstract: Background/Purpose: Ketamine has recently emerged as a promising therapeutic alternative for abortive migraine therapy, likely secondary to N-methyl-D-aspartate antagonism. Most reports examine adults and the intravenous route. Fewer utilize intranasal administration or pediatric populations. Given limited evidence for intranasal ketamine in pediatric migraine populations, we retrospectively reviewed our experience to further characterize safety and efficacy of IN ketamine in this population Methods: A retrospective review in a free-standing, pediatric medical center was performed examining the utilization of intranasal ketamine at 0.1-0.2 mg/kg/dose up to 5 doses in pediatric migraineurs. Pain scores (scale = 0–10) were recorded at baseline and after each dose. Response was characterized as pain score reduction to 0–3 and/or reduction of at least 50%. Results: Twenty-five encounters (25/34; 73.5%) were responders (mean pain score reduction of -7.2 from admission to treatment completion). Overall pain reduction from admission to discharge in the entire study population was 66.1%. Side effects were mild and transient. Conclusions: Our experience with intranasal ketamine has promising outcomes in both pain relief and side effect minimization. When other therapeutic options are unavailable, practitioners should consider intranasal ketamine. Abstract Word Count: 185
Key Words: adolescents; children; efficacy; headache; ketamine; migraine; NMDA antagonist; treatment Abbreviations: ED, emergency department; NSAIDs, nonsteroidal anti-inflammatory drugs; DHE, dihydroergotamine; NMDA, N-methyl-D-aspartate; IN, intranasal; IV, intravenous Declarations of Interest: None. 2
Introduction Migraine in adolescents and children is a common reason for presentation to emergency departments (EDs) and inpatient admission. 1,2 It is often treated with nonsteroidal antiinflammatory drugs (NSAIDs), dopamine receptor antagonists, triptans, or dihydroergotamine (DHE). Some cases, however, are refractory to traditional medications and options become narrowed.1,2 Oftentimes, patients may utilize a triptan at home which would subsequently eliminate DHE as a second line option due to contraindication in which concomitant use would result in enhanced vasoconstriction.3 Restricting therapy further, DHE, commonly employed for treatment of status migrainosus, has intermittently been in short supply. Fortunately, this shortage is currently resolved.4
Ketamine, a lipophilic, rapid-acting, N-methyl-D-aspartate (NMDA) antagonist, has emerged as a promising therapeutic alternative for abortive migraine therapy.5,6 Excitatory glutamate signaling may be inhibited by ketamine via NMDA antagonism, and this action could suppress cortical spreading depression and alleviate migraines7 – potentially even those with aura.6 This action is meaningful as ketamine could provide an alternative mechanism in which cortical spreading depression could be minimized and migraines may be alleviated.
Reports in mixed migraine patient populations described statistically significant pain score reductions (7.1 to 3.8; p<0.0001) with intermittent intravenous (IV) ketamine8 and diminished severity with ketamine infusions (0.12-0.42 mg/kg/hour)9 without serious adverse effects (AEs).8,9 Interestingly, reports utilizing the intranasal (IN) route suggest this method may be effective in migraine treatment and, in some cases, could circumvent the need for IV access.5,915
IN ketamine 25 mg in migraine patients with prolonged aura demonstrated statistically
significant reduced aura severity (p=0.032) compared to midazolam. Though midazolam is an 3
active substance, it was chosen as the control by the authors for its relative lack of efficacy for migraine, but similar psychoactive effects to ketamine allowing for realistic treatment blinding.6 Reports of efficacy and safety with IN ketamine (0.3-0.5 mg/kg/dose) in pediatric patients with various pain diagnoses have been published.10-15 An initial case report of IN ketamine for pediatric migraine at our institution demonstrated promise in therapeutic success and safety profile16, but data and statistical analysis in this population are still lacking. Utilization of IN ketamine for treatment of migraine at our institution was applied secondary to limited availability of DHE as part of our routine treatment protocol (i.e. hydration, ketorolac, and metoclopramide or prochlorperazine ± diphenhydramine).
Given limited evidence for IN ketamine in pediatric migraine populations, we retrospectively reviewed our experience to further characterize safety and efficacy of IN ketamine in this population. We hypothesized that IN ketamine would be both a safe and efficacious alternative therapy for abortive migraine therapy in the pediatric migraineur population.
Methods Study Design and Data Collection A retrospective chart review of electronic medical records was conducted at Cook Children’s Medical Center (CCMC; Fort Worth, TX, USA) from December 2016 through October 2017. The study was approved and a waiver of informed consent was granted by the Cook Children’s Health Care System Institutional Review Board (IRB # 2017-050). Patients aged 18 years and younger deemed by ED, pain, or neurology physicians to have status migrainosus as the presenting complaint and receiving IN ketamine were included for analysis. Patients were excluded if they received IN ketamine but later were found to have headache of another etiology 4
or if doses were refused after treatment initiation for reasons other than efficacy or side effects. If a patient presented more than once for IN ketamine, only the first encounter was utilized to avoid data clustering. The primary endpoints of this review were to establish efficacy specifically migraine pain reduction or resolution - of IN ketamine therapy and to assess its safety in pediatric migraineurs.
A standard data collection form was used to ensure consistency and accuracy in the information collected. Data collected for each encounter included: age; weight; sex; duration of migraine prior to presentation (days); comorbid conditions; previously trialed home and hospitaladministered anti-migraine medications; relevant medical history; admission location (inpatient versus ED); length of stay; ketamine dosage; number of ketamine doses administered; pain scores prior, during, and after ketamine administration; vital signs during and after ketamine administration; patient reported side effects; medications utilized after IN ketamine; and readmissions. Duration of migraine prior to hospital presentation was based on the patient’s or parents’ subjective report. Diagnosis of migraine (i.e. aura versus no aura; chronic versus episodic) was recorded from discharge diagnoses specified on the patient’s medical record and subsequently reassessed by a neurologist (BR) from the present study for accuracy. Episodic migraine (duration <15 days) and chronic migraine (duration > 15 days) were defined by the ICHD-3 criteria.17 Patient pain outcomes during each encounter were recorded until discharge; side effect monitoring was recorded during and up to one hour after IN ketamine administration.
Physicians assigned IN ketamine based on individual, clinical judgment. Patients received IN ketamine doses of 0.1-0.2 mg/kg/dose (maximum initial dose: 10 mg; maximum subsequent doses: 25 mg) every 15 minutes up to 5 doses. Ketamine formulations utilized were IV 10mg/mL and 100 mg/mL products. The ketamine 100 mg/mL formulation was utilized to 5
minimize volume requirements with higher doses to maximize patient comfort. A nasal atomizer (MAD Nasal™; Teleflex Medical) was attached to the syringe for administration.18 To prime the atomizer, 0.1 mL was provided as overfill for priming volume. Physicians were present for administration of the first dose; subsequent doses could be administered without physician presence.
Pain scores were assessed on admission, just prior to ketamine administration, with each dose of IN ketamine, at the end of IN ketamine treatment, and at discharge. Patient reported pain scores were determined via a numeric pain scale of 0 (no pain) to 10 (most severe pain).19 Patients were deemed “responders” if (1) pain score upon completion of ketamine therapy and/or discharge was defined as 0-3 (no to mild pain) and/or (2) patient pain score reduction of >50% from admission to completion of ketamine therapy. Vital signs and patient reported side effects were assessed at each ketamine dose and intermittently up to one hour after the last ketamine dose was administered. Vital signs were considered abnormal if values fell above or below age-specific ranges recommended by both the American Heart Association Pediatric Advanced Life Support Guidelines and the National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents.20,21 Readmission was defined as representation to the CCMC ED or another CCMC inpatient admission for complaints of migraine within 72 hours of discharge.
Statistical Analysis Data was analyzed via the independent, two-tailed t-test and one-way ANOVA between encounters with a p-value <0.05 utilizing IBM SPSS software. Assumptions required to interpret the statistics have been met via utilization of Levene’s test for equality of variances. Mean and standard deviation were used as the measure of central tendency and variability for analysis. 6
No statistical power calculation was conducted prior to the study as the sample size was based on the available data. The authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Results Forty-six encounters with orders for IN ketamine between December 2016 and October of 2017 were identified. Seven were excluded due to diagnosis of headache of a secondary etiology (n=3), refusal of doses for reasons other than side effects (n=1), initiation of ketamine with a pain score of zero (n=1), and non-administration of ketamine despite medication orders (n=2). Five other encounters from three patients were not included on analysis as these were subsequent administrations of IN ketamine separated by >72 hours. Ultimately, a total of 34 patients in status migrainosus meeting inclusion criteria were examined. Of these, 25/34 (73.5%) were classified as responders and 9/34 (26.5%) were non-responders (Figure 1).
* refused discharge, n=1; admission secondary to hand/food pain despite migraine resolution, n=1
Figure 1: Encounter treatment stratification 7
At baseline, patients in each group were fairly similar and reflective of a typical pediatric migraineur population – majority adolescent females, similar mean weight, and similar race/ethnicity stratification (Table 1). Responder n=25
Non-responder n=9
p value
14.6 ± 2.6
16.2 ± 2.3
0.106
4 21
0 9
0.201
19 4 2
8 1 0
67.8 ± 23.2
74.7 ± 23.6
0.449
20.3 ± 30.1
36.9 ± 65.7
0.484
Chronic
14
6
0.577
Episodic
11
3
6
1
0.412
1.7 ± 1.9
3.6 ± 1.81
0.015
Patient population †
Age (years) Sex Male Female Race/ethnicity Caucasian/Non-Hispanic Caucasian/Hispanic African American †
Weight (kg) † Duration of migraine prior to presentation (days) Migraine classification
Migraine with aura †
Length of stay (days) Abbreviations: kg, kilogram; SD, standard deviation † reported as mean ± SD
0.617
Table 1: Patient demographics and descriptive statistics of the patient population in the study
Duration of migraine prior to presentation was not statistically significant between groups. In addition, there was not statistically significant difference between responders and nonresponders when stratifying diagnoses of migraine with or migraine without aura (p=0.412) and episodic or chronic migraine (p=0.577). Additionally, both responders and non-responders trialed several medications prior to IN ketamine. Responders trialed a mean number of 8.68 medications while non-responders trialed a mean number of 7.7 medications since migraine onset (both prophylactic and abortive). This difference, however, was not statistically significant. The most commonly utilized medications included NSAIDs (94.1%), fluids (85.3%), dopamine
8
receptor antagonists (73.5%), diphenhydramine (79.4%), antidepressants (55.9%), ondansetron (52.9%), triptans (41.2%), DHE (35.3%), and magnesium (32.4%).
Responders and non-responders each received average IN ketamine doses of 0.14 mg/kg/dose. However, responders received a mean total dose of 30.2 mg while non-responders received a mean total dose of 45.8 mg (p=0.009).
Baseline pain scores between groups (responder: 8.6 vs non-responder: 8.8) were equitable and not significant. Significant differences between responders and non-responders were observed in mean pain scores immediately after ketamine dose 1 (5 vs 7.4; p=0.0149), dose 2 (3.1 vs 7.3; p=0.001), dose 3 (2.9 vs 7.1; p=0.001), dose 4 (1.3 vs 7.4; p<0.001), and dose 5 (2.3 vs 6.9; p=0.009) (Figure 2).
9
Figure 2: Pain response per dose – Statistically significant reduction in average pain scores in responders after each dose of intranasal ketamine. Examining when responders actually achieved a response, 36% achieved response at dose 1, 60% by dose 2, 76% by dose 3, 92% by dose 4, and 100% at dose 5. Ultimately, responders had a mean pain score reduction of -7.2 from admission to completion of ketamine treatment. There were statistically significant differences between admission and final pain scores at the completion of ketamine between responders and non-responders (1.4 vs. 7.3, respectively; p<0.001) (Figure 3).
Figure 3: Final pain scores after intranasal ketamine – Statistically significant difference in final pain score of headaches in responders versus non-responders after completion of intranasal ketamine. 10
Notably, a 66.1% reduction in pain was seen overall (83.7% reduction in responders vs 16.6% in non-responders) (Figure 4).
Figure 4: Percent pain reduction with intranasal ketamine – Statistically significant difference in the percent reduction in pain scores between responders and non-responders (i.e. starting pain score of 8 reduced to ending score of 2 = 75% pain reduction) from admission to end of treatment.
Twenty-two patients initiated treatment with IN ketamine in the ED. Of these 22 encounters, 15/24 (68.2%) responded to therapy and were subsequently discharged home. Of 12 encounters with ketamine inpatient initiation, 8/12 (66.7%) responded and did not require further treatment. 11
Dizziness (n=2), dysphoria (n=3), and nausea (n=1) were reported by patients in both groups. No flushing was noted in either group. Most patients experienced some hypertension or tachypnea. However, all side effects and vital sign aberrations were mild and none were statistically significant (Table 2; Table 3). Side effects
Responder n=25
Non-responder n=9
p-value
1 (4%) 2 (8%) 0 0
1 (11.1%) 1 (11.1%) 0 1 (11.1%)
0.465 0.616 -0.265
Dizziness Dysphoria Flush/feel hot Nausea
Table 2: Patient reported side effects – No differences seen between responders and nonresponders.
Systolic BP max (mmHg)
120
Responders* n=25 † 123.4 (101-148)
Systolic BP min (mmHg) Diastolic BP max (mmHg)
90 90
109.3 (81-139) † 79.7 (52-139)
Diastolic BP min (mmHg)
70
65.3 (52-83)
HR max (beats/min) HR min (beats/min)
100 60
91.6 (70-130) 77.5 (58-117)
Vital Signs
Normal
†
†
Non-responders* n=9 119.4 (105-139) 101.2 (66-122) 78.4 (65-97) 60.8 (49-71) 90.3 (54-116) 76.4 (47-104)
RR max (breaths/min) 17 20.3 (14-30) 20.2 (18-26) RR min (breaths/min) 11 16.3 (12-20) 15.2 (10-18) Abbreviations: BP, blood pressure; HR, heart rate; RR, respiratory rate; max, maximum; min, minimum *reported as mean (range) † n=24; blood pressure not assessed on one patient
Table 3: Vital signs with intranasal ketamine treatment – No differences seen between responders and non-responders during and up to one hour after completion of treatment.
No side effects were treatment limiting nor did they correlate with any specific dose number during the treatment course. No statistically significant differences in readmissions were seen between responders and non-responders. No patient appeared to develop patterns of abuse or signs of tolerance. 12
Discussion In this single-institution, retrospective chart review of pediatric migraineurs, IN ketamine was found to be efficacious and safe - evidenced by the percentage of patients exhibiting clinical improvement of migraine and low incidence of major or therapy limiting side effects. This is quite meaningful for subsets of patients who do not respond optimally or at all to conventional abortive migraine therapy. The difference between responders and non-responders pain scores from admission to discharge was clinically and statistically significant. Overall pain scores were reduced from 8.6 on admission to 3.4 immediately following IN ketamine treatment completion. Furthermore, responders had an average pain score reduction from 8.6 on admission to 1.4 at discharge. These results are similar to previous reports with IV ketamine.8,9 Lauritsen et al. utilized ketamine infusions (mean rate of 0.34 mg/kg/hr) for at least 8 hours in six adult patients with refractory chronic migraine to target a pain score of 3 or less. Similar to our pediatric population, the majority of patients enrolled in the Lauritsen study were female. All six patients achieved the target. However, much higher total doses and longer durations were utilized (0.120.41 mg/kg/hr over 12-82 hours).9 Pomeroy et al. utilized ketamine infusions (mean infusion duration = 4.8 days) to treat refractory migraine in adults which resulted in average pain score reduction from 7.1 on admission to 3.8 at discharge (p<0.0001).8 Afridi et al. reported statistically significant reduction in aura severity (and, thus, theoretical control of cortical spreading depression with subsequent clinical improvement) in eighteen patients with migraine after 25mg dose of IN ketamine.6 We did not report reduction in aura severity, but we did note statistically significant clinical improvement in migraine pain. Specifically, pain scores were significantly reduced in approximately 73.5% of our patient population. Our results, in combination with current literature, supports the efficacy of ketamine as a novel migraine therapeutic option targeting glutamatergic inhibition via NMDA-receptor antagonism.
13
Of note, some patients could confound our results. One patient (classified as a responder due to the resolution of migraine) presented with simultaneous migraine and hand/foot pain. The migraine subsided completely with IN ketamine, but the hand/food pain persisted. This resulted in pain scores with no change from admission to discharge despite migraine resolution. A second patient the patient was initially treated in the ED with IN ketamine and had complete resolution of the migraine at the end of the treatment course. However, the parent refused discharge and was subsequently admitted.
IN ketamine’s place in abortive migraine therapy is still undefined. Current pediatric recommendations generally indicate DHE as the standard of care. Our findings on migraine pain reduction present a valid argument to consider incorporation of IN ketamine into abortive migraine therapy regimens, especially bearing in mind the similarity to Linder et al.’s results and recommendations with IV DHE in pediatric patients. Linder et al. described excellent treatment response in 24 (80%) patients utilizing DHE. Excellent response in this study was defined as >90% reduction in headache intensity or frequency or a >75% reduction in both.22 Using our definition of response, this increased to nearly 90%. A slightly lower, but still clinically significant, amount of patient encounters (73.5%) in our study were classified as responders. It is also important to note the considerable differences in each study’s baseline demographics. Linder et al. performed extensive screenings and exclusions prior to DHE administration.22 In their study, baseline demographics were comparably less refractory to our patient population. In fact, individuals in our study had typically failed multiple standard pharmacologic treatments prior to receiving IN ketamine – the majority of these medications being acetaminophen, antihistamines, antidepressants, DHE, dopamine receptor antagonists, fluid/hydration, NSAIDs, and/or triptans. Linder’s less refractory patient population could have promoted their slightly higher response rate. 14
No IN ketamine dose limit or optimized regimen has been determined. While this study was not designed to do so, efficacy does not appear to correlate to higher doses. Indicators may hint at individual response versus non-response. Significant differences in pain scores between responders and non-responders were noted at each dose. Non-responders appeared to have a small initial pain score reduction on dose one, but subsequent doses resulted in a plateau in pain response. The paradoxical initial decrease cannot be ruled out as potential placebo effect. Conversely, responders appeared to have mean pain reduction on each subsequently administered dose (Figure 2). This difference is useful to note when taken into account with the significant difference in doses administered between groups. It is reasonable to deduce that if a patient is going to respond, they will do so by the 5th dose, and the majority will likely respond by doses 2 and 3 (60% and 76%, respectively, in the present study). Further studies with precise dosing protocols and controls are warranted to truly examine the optimal number of doses and likely time to response.
Notably, repeat courses greater than 72 hours apart do not appear to correlate to tolerance or patterns of abuse. Patients receiving two or more separate IN ketamine courses were excluded from primary analysis, but data was collected to assess subsequent responses for tolerance and potential patterns for abuse. Two patients returned for subsequent doses – each treatment course separated by nearly 4 weeks. One individual received three different courses of IN ketamine with excellent response on courses one and two. It was only on the third occurrence that the individual did not respond to IN ketamine. No definitive description could be provided by these scenarios, but anecdotally, patients appear to respond despite previous doses.
15
Other considerations with migraine treatment are rebound headaches. Zitek, et al. may provide some insight into extended efficacy of ketamine after the patient is discharged home.23 In their study, patients received either prochlorperazine with diphenhydramine or ketamine with ondansetron. At a 24 to 48 hour follow-up, they noted 6/20 (30%) of patients who received prochlorperazine reported a headache, and 9/18 (50%) of patients who received ketamine reported headache – a difference of 20% (95% CI -10.6% to 50.6%).23 While our present study was unable to assess for rebound headaches due to availability of data, we did not record any instance of readmission. Data was not available for readmissions to different facilities, so this may limit proper assessment of true readmission rates. However, it is promising that there were not statistically significant differences in readmission rates to our facility between responders and non-responders.
The avoidance of admission seen with IN ketamine administration in the ED (77.3%) in this present study is potentially advantageous – both fiscally and clinically. Typically, patients are admitted for subsequent DHE dosing if one dose in the ED does not suffice and remain admitted until the migraine resolves. This admission can take several days and involve several dose changes. IN ketamine provides first-tier therapy alternative before resorting to admission. Additionally, in patients whom IN ketamine was initiated in the inpatient setting, pain resolution was sustained long enough to deem the patient stable for discharge. This may ultimately reduce inpatient length of stay in contrast to repeated doses needed for DHE, valproic acid, or other commonly utilized migraine therapies. It is noteworthy to briefly comment on the ED to inpatient admission rate, though. Current literature reports admission rates from the ED to be approximately 7%.24,25 Our ED to inpatient admission rate appeared to be much more frequent (~22.7%); however, our study did not include patients who responded to lower tier treatments (i.e. fluid boluses, dopamine receptor antagonists, NSAIDs) into the total admission calculation 16
whereas previous literature encompassed all potential treatment options. Because a large portion of responders to other therapies were not included in the study, the ED to inpatient admission rate at the present institution was likely much lower than reported. Clinicians should relate our results to their own practice appropriately, but the potential efficacy of IN ketamine should not necessarily be discounted.
Psychotropic, psychedelic, cardiovascular, and hepatic effects have been noted with long term and higher doses of ketamine.9,26,27 Concern for these potential sequelae were largely quelled with the acute, subanesthetic regimen utilized in the present study. Side effects seen were similar to but fewer in number than those reported in current literature. Andolfatto et al. reported mild and transient episodes of dizziness (53%), feeling of unreality (35%), nausea (10%), mood change (8%), and changes in hearing (1%) in adult and pediatric patients (n=40) receiving comparatively higher doses (0.5-0.75 mg/kg/dose) to our study.11 Patients in our study also experienced dizziness (5.6%, n=2/36), dysphoria (8.3%, n=3/36) , and nausea (2.8%, N=1/36), but at much lower rates. Etchison et al. also reported their safe experience with low-dose IV ketamine versus placebo.28 Ketamine, unsurprisingly, had statistically significantly higher Side Effects Rating Scale for Dissociative Anesthetics (SERSDA) scores for fatigue and generalized discomfort compared to placebo; otherwise, all other SERDA score differences were not statistically significant.28 Development of tolerance and patterns of abuse are additional common concerns with ketamine utilization. No patient in the present study appeared to develop either of these for the duration of the study. Caution and more robust studies are still warranted as the present study examines a relatively small cohort over a short duration and does not follow these patients longitudinally. In this particular study, though, ketamine – especially in low doses – appears to be a reasonably safe treatment option with low risk for dependence, even when
17
given after multiple other pharmacologic agents. Monitoring is still encouraged and supported by these results.
IN ketamine offers a major benefit over current traditional migraine protocols: no need for IV access. Current traditional migraine protocols not only require IV access, but may require approximately 1 to 2 hours for one course, and often include multiple doses of fluids, NSAIDs, diphenhydramine, dopamine receptor antagonists, DHE, and/or various other therapeutic alternatives. In contrast, a full course of IN ketamine may be administered in under an hour and requires no IV access nor premedication. These reduce risk of infection, medication exposure, and side effects, decrease time to potential reduction of pain, and expedite readiness for discharge. Protocols utilizing DHE carry several risks (i.e. dystonia, extreme nausea, hypertension, and injection site reactions) and cannot be initiated until at least 24 hours after a triptan has been administered. These risks and limitations are avoided with IN ketamine. Superiority or noninferiority to current standards of care cannot be discerned with current results, but defining IN ketamine as a first tier agent alternative to DHE should not be ruled out, especially considering the aforementioned benefits.
To date, this is one of the largest studies examining IN ketamine for abortive migraine treatment and is the only report of IN ketamine in pediatric patients for abortive migraine treatment. This is the primary analysis, and this data has not previously been published in any form. The retrospective nature (i.e. limited or no depression score records; inability to standardize; no true head to head comparison with other therapeutic options) of this study is limiting. Despite these shortcomings, our study provides meaningful insight on a previously unreported yet seemingly viable and effective therapeutic regimen for a pediatric migraineur population that has limited treatment options. 18
Future studies to examine most effective regimen as well as sequence within current guideline recommendations are warranted. Head-to-head comparison with current standards of care, such as triptans and DHE, would further delineate IN ketamine’s true place within the abortive migraine treatment pathway. For instance, a randomized, prospective head-to-head comparison of DHE and IN ketamine in patients presenting to an ED for abortive migraine therapy would be especially useful. Alternative designs could include patients presenting to an ED for abortive migraine therapy; those with a contraindication to DHE would be assigned to IN ketamine while the remainder would receive IV DHE as usual. Efficacy could then be more accurately compared in both designs. Additional studies of merit include examining long term effects such as depression scores, psychological side effects, tolerance, instances of rebound migraines, and propensity toward patterns of abuse given ketamine’s social stigma.
Practitioners should consider integration of IN ketamine into abortive migraine therapy algorithms. Our experience has promising outcomes in both pain relief and minimization of unwanted, secondary effects. Pediatric migraineurs now have multiple, viable treatment options, and IN ketamine – defined by its potential efficacy, safety, quick onset, and non-invasive nature – provides one that is particularly desirable.
Acknowledgements: Kimberly Tobin, PharmD; Dani Ball, PharmD, BCPPS Author Contributions: AT contributed to design, implementation, data collection, data analysis, interpretation, and created the first draft of the manuscript. SS contributed to design, data analysis, interpretation, and provided meaningful feedback on subsequent versions of this work. EM and MSP contributed to design, data analysis, interpretation, and ongoing edits to the work. 19
BR contributed to design, data clarification, data analysis, interpretation, and ongoing edits to the work. Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Ethical Approval: Approval and a waiver of informed consent was granted by the Cook Children’s Health Care System Institutional Review Board (IRB # 2017-050)
References: [1] Gelfand AA, Goadsby PJ. Treatment of pediatric migraine in the emergency room. Pediatr Neurol. 2012 Oct; 47(4):233-41. [2] Lewis D, Ashwal S, Hershey A, et al. Practice parameter: pharmacological treatment of migraine headache in children and adolescents. Neurology. 2004 Dec 28; 63(12):221524. [3] Dihydroergotamine mesylate (DHE 45) injection, USP. Bridgewater (NJ): Valeant Pharmaceuticals; 2017 Nov. Package insert. NDC 66490-041-01. [4] FDA Drug Shortages: Current and Resolved Drug Shortages and Discontinuations Reported to FDA [Internet]. Silver Spring(MD): U.S. Food and Drug Administration. Dihydroergotamine Mesylate Injection; [cited 2017 Feb 14]; [about 1 screen]. Available from: http://www.accessdata.fda.gov/scripts/drugshortages/ [5] Ketamine hydrochloride. Micromedex ® [Internet]. Greenwood Village (CO): Truven Health Analytics. 1974-2017 [cited 2017 Feb 4]. Available from: http://www.micromedexsolutions.com/ [6] Afridi SK, Giffin NJ, Kaube H, et al. A randomized controlled trial of intranasal ketamine in migraine with prolonged aura. Neurology. 2013 Feb 12; 80(7):642-7. 20
[7] Hoffman J, Charles A. Glutamate and its receptors as therapeutic targets for migraine. Neurotherapeutics. 2018 Apr; 15(2):361-70. [8] Pomeroy JL, Marmura MJ, Nahas SJ, et al. Ketamine infusions for treatment refractory headache. Headache. 2017 Feb (2):276-82. [9] Lauritsen C, Mazuera S, Lipton RB, et al. Intravenous ketamine for subacute treatment of refractory chronic migraine: a case series. J Headache Pain. 2016 Dec; 17(1):106. [10] Yeaman F, Oakley E, Meek R, et al. Sub-dissociative dose intranasal ketamine for limb injury pain in children in the emergency department: a pilot study. Emerg Med Australas. 2013 Apr; 25(2):161-7. [11] Andolfatto G, Willman E, Joo D, et al. Intranasal ketamine for analgesia in the emergency department: a prospective observational series. Acad Emerg Med. 2013 Oct; 20(10):1050-4. [12] Nielsen BN, Friis SM, Rømsing J, et al. Intranasal sufentanil/ketamine analgesia in children. Paediatr Anaesth. 2014 Feb; 24(2):170-80. [13] Graudins A, Meek R, Egerton-Warburton D, et al. The PITCHFORK (Pain in Children Fentanyl or Ketamine) trial: a randomized controlled trial comparing intranasal ketamine and fentanyl for the relief of moderate to severe pain in children with limb injuries. Ann Emerg Med. 2015 Mar; 65(3):248-54. [14] Shrestha R, Pant S, Shrestha A, et al. Intranasal ketamine for the treatment of patients with acute pain in the emergency department. World J Emerg Med. 2016; 7(1):19-24. [15] Surendar MN, Pandey RK, Saksena AK, et al. A comparative evaluation of intranasal dexmedetomidine, midazolam, and ketamine for their sedative and analgesic properties: a triple blind randomized study. J Clin Pediatr Dent. 2014 Spring; 38(3):255-61. [16] Turner AL, Tobin K, Miller E, et al. Intranasal ketamine for abortive migraine therapy in pediatric patients: a case series [abstract]. Cephalalgia. 2017 Sept; 27(1 Suppl):33. 21
[17] Olesen J, Bendtsen L, Dodick D, et al. Headache Classification Committee of the International Headache Society: The international classification of headache disorders, 3rd edition. Cephalalgia. 2018; 38(1):1-211. [18] Teleflex®: A Global Provider of Medical Technologies [Internet]. Wayne(PA): Teleflex Incorporated. Atomization: MAD Nasal™ Intranasal Mucosal Atomization Device; [cited 2019 Oct 5]; [about 1 screen]. Available from: https://www.teleflex.com/usa/en/productareas/anesthesia/atomization/mad-nasal-device/index [19] Jensen MP, Karoly P, Braver S. The measurement of clinical pain intensity: a comparison of six methods. Pain. 1986; 27:117-26. [20] National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation and treatment of high blood pressure in children and adolescents. Pediatrics. 2004 Aug; 114(2 Suppl 4th Report):555-76. [21] American Heart Association. Pediatric Advanced Life Support Provider Manual. American Heart Association; 2016. [22] Linder SL. Treatment of childhood headache with dihydroergotamine mesylate. Headache. 1994 Nov-Dec; 34(10):578-80. [23] Zitek T, Gates M, Pitotti C, et al. A comparison of headache treatment in the emergency department: prochlorperazine versus ketamine. Ann Emer Med. 2018 Mar 1; 71(3):36977.e1. [24] Kabbouche M. Pediatric inpatient headache therapy: what is available. Headache. 2015 Nov-Dec; 55(10):1426-9. [25] Kabbouche MA, Linder SL. Management of migraine in children and adolescents in the emergency department and inpatient setting. Curr Pain Headache Rep. 2005 Oct; 9(5):363-7. 22
[26] Niesters M, Martini C, Dahan A. Ketamine for chronic pain: risk and benefit. Br J Clin Pharmacol. 2014 Feb; 77(2):357-67. [27] Wilkinson ST, Sanacora G. Considerations on the off-label use of ketamine as a treatment for mood disorders. JAMA. 2017 Sep 5;318(9):793-4. [28] Etchison A, Manfredi L, Mohammed M, et al. Low-dose intravenous ketamine for acute migraine in the emergency department: a randomized placebo-controlled trial [abstract]. Ann Emer Med. 2017 Oct; Suppl: 70(4):S84.
23
S0887-8994(19)30924-5
DOI:
https://doi.org/10.1016/j.pediatrneurol.2019.10.007
Reference:
PNU 9680
To appear in:
Pediatric Neurology
Received Date: 4 June 2019 Revised Date:
16 October 2019
Accepted Date: 27 October 2019
Please cite this article as: Turner AL, Shandley S, Miller E, Perry MS, Ryals B, Intranasal ketamine for abortive migraine therapy in pediatric patients: a single-center, retrospective review, Pediatric Neurology (2019), doi: https://doi.org/10.1016/j.pediatrneurol.2019.10.007. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
Title: Intranasal ketamine for abortive migraine therapy in pediatric patients: a single-center, retrospective review Running Title: Intranasal ketamine for migraine
Authors: Adrian L. Turner, PharmDa†; Sabrina Shandley, PhD, PMPb; Ean Miller, PharmD, BCPPSa; M. Scott Perry, MDc; Brian Ryals, MDc
Corresponding Author: † [email protected]; 801 7th Avenue, Fort Worth, TX 76104, USA Affiliations 1 2 3 a
Department of Pharmacy, Cook Children’s Medical Center, Fort Worth, TX, USA
b
Research Administration Office, Cook Children’s Medical Center, Fort Worth, TX, USA
c
Jane and John Justin Neurosciences Center, Cook Children’s Medical Center, Fort Worth, TX,
USA
Manuscript Word Count: 3760 Table and Figure Count: 3 tables; 4 figures
1
Abstract: Background/Purpose: Ketamine has recently emerged as a promising therapeutic alternative for abortive migraine therapy, likely secondary to N-methyl-D-aspartate antagonism. Most reports examine adults and the intravenous route. Fewer utilize intranasal administration or pediatric populations. Given limited evidence for intranasal ketamine in pediatric migraine populations, we retrospectively reviewed our experience to further characterize safety and efficacy of IN ketamine in this population Methods: A retrospective review in a free-standing, pediatric medical center was performed examining the utilization of intranasal ketamine at 0.1-0.2 mg/kg/dose up to 5 doses in pediatric migraineurs. Pain scores (scale = 0–10) were recorded at baseline and after each dose. Response was characterized as pain score reduction to 0–3 and/or reduction of at least 50%. Results: Twenty-five encounters (25/34; 73.5%) were responders (mean pain score reduction of -7.2 from admission to treatment completion). Overall pain reduction from admission to discharge in the entire study population was 66.1%. Side effects were mild and transient. Conclusions: Our experience with intranasal ketamine has promising outcomes in both pain relief and side effect minimization. When other therapeutic options are unavailable, practitioners should consider intranasal ketamine. Abstract Word Count: 185
Key Words: adolescents; children; efficacy; headache; ketamine; migraine; NMDA antagonist; treatment Abbreviations: ED, emergency department; NSAIDs, nonsteroidal anti-inflammatory drugs; DHE, dihydroergotamine; NMDA, N-methyl-D-aspartate; IN, intranasal; IV, intravenous Declarations of Interest: None. 2
Introduction Migraine in adolescents and children is a common reason for presentation to emergency departments (EDs) and inpatient admission. 1,2 It is often treated with nonsteroidal antiinflammatory drugs (NSAIDs), dopamine receptor antagonists, triptans, or dihydroergotamine (DHE). Some cases, however, are refractory to traditional medications and options become narrowed.1,2 Oftentimes, patients may utilize a triptan at home which would subsequently eliminate DHE as a second line option due to contraindication in which concomitant use would result in enhanced vasoconstriction.3 Restricting therapy further, DHE, commonly employed for treatment of status migrainosus, has intermittently been in short supply. Fortunately, this shortage is currently resolved.4
Ketamine, a lipophilic, rapid-acting, N-methyl-D-aspartate (NMDA) antagonist, has emerged as a promising therapeutic alternative for abortive migraine therapy.5,6 Excitatory glutamate signaling may be inhibited by ketamine via NMDA antagonism, and this action could suppress cortical spreading depression and alleviate migraines7 – potentially even those with aura.6 This action is meaningful as ketamine could provide an alternative mechanism in which cortical spreading depression could be minimized and migraines may be alleviated.
Reports in mixed migraine patient populations described statistically significant pain score reductions (7.1 to 3.8; p<0.0001) with intermittent intravenous (IV) ketamine8 and diminished severity with ketamine infusions (0.12-0.42 mg/kg/hour)9 without serious adverse effects (AEs).8,9 Interestingly, reports utilizing the intranasal (IN) route suggest this method may be effective in migraine treatment and, in some cases, could circumvent the need for IV access.5,915
IN ketamine 25 mg in migraine patients with prolonged aura demonstrated statistically
significant reduced aura severity (p=0.032) compared to midazolam. Though midazolam is an 3
active substance, it was chosen as the control by the authors for its relative lack of efficacy for migraine, but similar psychoactive effects to ketamine allowing for realistic treatment blinding.6 Reports of efficacy and safety with IN ketamine (0.3-0.5 mg/kg/dose) in pediatric patients with various pain diagnoses have been published.10-15 An initial case report of IN ketamine for pediatric migraine at our institution demonstrated promise in therapeutic success and safety profile16, but data and statistical analysis in this population are still lacking. Utilization of IN ketamine for treatment of migraine at our institution was applied secondary to limited availability of DHE as part of our routine treatment protocol (i.e. hydration, ketorolac, and metoclopramide or prochlorperazine ± diphenhydramine).
Given limited evidence for IN ketamine in pediatric migraine populations, we retrospectively reviewed our experience to further characterize safety and efficacy of IN ketamine in this population. We hypothesized that IN ketamine would be both a safe and efficacious alternative therapy for abortive migraine therapy in the pediatric migraineur population.
Methods Study Design and Data Collection A retrospective chart review of electronic medical records was conducted at Cook Children’s Medical Center (CCMC; Fort Worth, TX, USA) from December 2016 through October 2017. The study was approved and a waiver of informed consent was granted by the Cook Children’s Health Care System Institutional Review Board (IRB # 2017-050). Patients aged 18 years and younger deemed by ED, pain, or neurology physicians to have status migrainosus as the presenting complaint and receiving IN ketamine were included for analysis. Patients were excluded if they received IN ketamine but later were found to have headache of another etiology 4
or if doses were refused after treatment initiation for reasons other than efficacy or side effects. If a patient presented more than once for IN ketamine, only the first encounter was utilized to avoid data clustering. The primary endpoints of this review were to establish efficacy specifically migraine pain reduction or resolution - of IN ketamine therapy and to assess its safety in pediatric migraineurs.
A standard data collection form was used to ensure consistency and accuracy in the information collected. Data collected for each encounter included: age; weight; sex; duration of migraine prior to presentation (days); comorbid conditions; previously trialed home and hospitaladministered anti-migraine medications; relevant medical history; admission location (inpatient versus ED); length of stay; ketamine dosage; number of ketamine doses administered; pain scores prior, during, and after ketamine administration; vital signs during and after ketamine administration; patient reported side effects; medications utilized after IN ketamine; and readmissions. Duration of migraine prior to hospital presentation was based on the patient’s or parents’ subjective report. Diagnosis of migraine (i.e. aura versus no aura; chronic versus episodic) was recorded from discharge diagnoses specified on the patient’s medical record and subsequently reassessed by a neurologist (BR) from the present study for accuracy. Episodic migraine (duration <15 days) and chronic migraine (duration > 15 days) were defined by the ICHD-3 criteria.17 Patient pain outcomes during each encounter were recorded until discharge; side effect monitoring was recorded during and up to one hour after IN ketamine administration.
Physicians assigned IN ketamine based on individual, clinical judgment. Patients received IN ketamine doses of 0.1-0.2 mg/kg/dose (maximum initial dose: 10 mg; maximum subsequent doses: 25 mg) every 15 minutes up to 5 doses. Ketamine formulations utilized were IV 10mg/mL and 100 mg/mL products. The ketamine 100 mg/mL formulation was utilized to 5
minimize volume requirements with higher doses to maximize patient comfort. A nasal atomizer (MAD Nasal™; Teleflex Medical) was attached to the syringe for administration.18 To prime the atomizer, 0.1 mL was provided as overfill for priming volume. Physicians were present for administration of the first dose; subsequent doses could be administered without physician presence.
Pain scores were assessed on admission, just prior to ketamine administration, with each dose of IN ketamine, at the end of IN ketamine treatment, and at discharge. Patient reported pain scores were determined via a numeric pain scale of 0 (no pain) to 10 (most severe pain).19 Patients were deemed “responders” if (1) pain score upon completion of ketamine therapy and/or discharge was defined as 0-3 (no to mild pain) and/or (2) patient pain score reduction of >50% from admission to completion of ketamine therapy. Vital signs and patient reported side effects were assessed at each ketamine dose and intermittently up to one hour after the last ketamine dose was administered. Vital signs were considered abnormal if values fell above or below age-specific ranges recommended by both the American Heart Association Pediatric Advanced Life Support Guidelines and the National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents.20,21 Readmission was defined as representation to the CCMC ED or another CCMC inpatient admission for complaints of migraine within 72 hours of discharge.
Statistical Analysis Data was analyzed via the independent, two-tailed t-test and one-way ANOVA between encounters with a p-value <0.05 utilizing IBM SPSS software. Assumptions required to interpret the statistics have been met via utilization of Levene’s test for equality of variances. Mean and standard deviation were used as the measure of central tendency and variability for analysis. 6
No statistical power calculation was conducted prior to the study as the sample size was based on the available data. The authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Results Forty-six encounters with orders for IN ketamine between December 2016 and October of 2017 were identified. Seven were excluded due to diagnosis of headache of a secondary etiology (n=3), refusal of doses for reasons other than side effects (n=1), initiation of ketamine with a pain score of zero (n=1), and non-administration of ketamine despite medication orders (n=2). Five other encounters from three patients were not included on analysis as these were subsequent administrations of IN ketamine separated by >72 hours. Ultimately, a total of 34 patients in status migrainosus meeting inclusion criteria were examined. Of these, 25/34 (73.5%) were classified as responders and 9/34 (26.5%) were non-responders (Figure 1).
* refused discharge, n=1; admission secondary to hand/food pain despite migraine resolution, n=1
Figure 1: Encounter treatment stratification 7
At baseline, patients in each group were fairly similar and reflective of a typical pediatric migraineur population – majority adolescent females, similar mean weight, and similar race/ethnicity stratification (Table 1). Responder n=25
Non-responder n=9
p value
14.6 ± 2.6
16.2 ± 2.3
0.106
4 21
0 9
0.201
19 4 2
8 1 0
67.8 ± 23.2
74.7 ± 23.6
0.449
20.3 ± 30.1
36.9 ± 65.7
0.484
Chronic
14
6
0.577
Episodic
11
3
6
1
0.412
1.7 ± 1.9
3.6 ± 1.81
0.015
Patient population †
Age (years) Sex Male Female Race/ethnicity Caucasian/Non-Hispanic Caucasian/Hispanic African American †
Weight (kg) † Duration of migraine prior to presentation (days) Migraine classification
Migraine with aura †
Length of stay (days) Abbreviations: kg, kilogram; SD, standard deviation † reported as mean ± SD
0.617
Table 1: Patient demographics and descriptive statistics of the patient population in the study
Duration of migraine prior to presentation was not statistically significant between groups. In addition, there was not statistically significant difference between responders and nonresponders when stratifying diagnoses of migraine with or migraine without aura (p=0.412) and episodic or chronic migraine (p=0.577). Additionally, both responders and non-responders trialed several medications prior to IN ketamine. Responders trialed a mean number of 8.68 medications while non-responders trialed a mean number of 7.7 medications since migraine onset (both prophylactic and abortive). This difference, however, was not statistically significant. The most commonly utilized medications included NSAIDs (94.1%), fluids (85.3%), dopamine
8
receptor antagonists (73.5%), diphenhydramine (79.4%), antidepressants (55.9%), ondansetron (52.9%), triptans (41.2%), DHE (35.3%), and magnesium (32.4%).
Responders and non-responders each received average IN ketamine doses of 0.14 mg/kg/dose. However, responders received a mean total dose of 30.2 mg while non-responders received a mean total dose of 45.8 mg (p=0.009).
Baseline pain scores between groups (responder: 8.6 vs non-responder: 8.8) were equitable and not significant. Significant differences between responders and non-responders were observed in mean pain scores immediately after ketamine dose 1 (5 vs 7.4; p=0.0149), dose 2 (3.1 vs 7.3; p=0.001), dose 3 (2.9 vs 7.1; p=0.001), dose 4 (1.3 vs 7.4; p<0.001), and dose 5 (2.3 vs 6.9; p=0.009) (Figure 2).
9
Figure 2: Pain response per dose – Statistically significant reduction in average pain scores in responders after each dose of intranasal ketamine. Examining when responders actually achieved a response, 36% achieved response at dose 1, 60% by dose 2, 76% by dose 3, 92% by dose 4, and 100% at dose 5. Ultimately, responders had a mean pain score reduction of -7.2 from admission to completion of ketamine treatment. There were statistically significant differences between admission and final pain scores at the completion of ketamine between responders and non-responders (1.4 vs. 7.3, respectively; p<0.001) (Figure 3).
Figure 3: Final pain scores after intranasal ketamine – Statistically significant difference in final pain score of headaches in responders versus non-responders after completion of intranasal ketamine. 10
Notably, a 66.1% reduction in pain was seen overall (83.7% reduction in responders vs 16.6% in non-responders) (Figure 4).
Figure 4: Percent pain reduction with intranasal ketamine – Statistically significant difference in the percent reduction in pain scores between responders and non-responders (i.e. starting pain score of 8 reduced to ending score of 2 = 75% pain reduction) from admission to end of treatment.
Twenty-two patients initiated treatment with IN ketamine in the ED. Of these 22 encounters, 15/24 (68.2%) responded to therapy and were subsequently discharged home. Of 12 encounters with ketamine inpatient initiation, 8/12 (66.7%) responded and did not require further treatment. 11
Dizziness (n=2), dysphoria (n=3), and nausea (n=1) were reported by patients in both groups. No flushing was noted in either group. Most patients experienced some hypertension or tachypnea. However, all side effects and vital sign aberrations were mild and none were statistically significant (Table 2; Table 3). Side effects
Responder n=25
Non-responder n=9
p-value
1 (4%) 2 (8%) 0 0
1 (11.1%) 1 (11.1%) 0 1 (11.1%)
0.465 0.616 -0.265
Dizziness Dysphoria Flush/feel hot Nausea
Table 2: Patient reported side effects – No differences seen between responders and nonresponders.
Systolic BP max (mmHg)
120
Responders* n=25 † 123.4 (101-148)
Systolic BP min (mmHg) Diastolic BP max (mmHg)
90 90
109.3 (81-139) † 79.7 (52-139)
Diastolic BP min (mmHg)
70
65.3 (52-83)
HR max (beats/min) HR min (beats/min)
100 60
91.6 (70-130) 77.5 (58-117)
Vital Signs
Normal
†
†
Non-responders* n=9 119.4 (105-139) 101.2 (66-122) 78.4 (65-97) 60.8 (49-71) 90.3 (54-116) 76.4 (47-104)
RR max (breaths/min) 17 20.3 (14-30) 20.2 (18-26) RR min (breaths/min) 11 16.3 (12-20) 15.2 (10-18) Abbreviations: BP, blood pressure; HR, heart rate; RR, respiratory rate; max, maximum; min, minimum *reported as mean (range) † n=24; blood pressure not assessed on one patient
Table 3: Vital signs with intranasal ketamine treatment – No differences seen between responders and non-responders during and up to one hour after completion of treatment.
No side effects were treatment limiting nor did they correlate with any specific dose number during the treatment course. No statistically significant differences in readmissions were seen between responders and non-responders. No patient appeared to develop patterns of abuse or signs of tolerance. 12
Discussion In this single-institution, retrospective chart review of pediatric migraineurs, IN ketamine was found to be efficacious and safe - evidenced by the percentage of patients exhibiting clinical improvement of migraine and low incidence of major or therapy limiting side effects. This is quite meaningful for subsets of patients who do not respond optimally or at all to conventional abortive migraine therapy. The difference between responders and non-responders pain scores from admission to discharge was clinically and statistically significant. Overall pain scores were reduced from 8.6 on admission to 3.4 immediately following IN ketamine treatment completion. Furthermore, responders had an average pain score reduction from 8.6 on admission to 1.4 at discharge. These results are similar to previous reports with IV ketamine.8,9 Lauritsen et al. utilized ketamine infusions (mean rate of 0.34 mg/kg/hr) for at least 8 hours in six adult patients with refractory chronic migraine to target a pain score of 3 or less. Similar to our pediatric population, the majority of patients enrolled in the Lauritsen study were female. All six patients achieved the target. However, much higher total doses and longer durations were utilized (0.120.41 mg/kg/hr over 12-82 hours).9 Pomeroy et al. utilized ketamine infusions (mean infusion duration = 4.8 days) to treat refractory migraine in adults which resulted in average pain score reduction from 7.1 on admission to 3.8 at discharge (p<0.0001).8 Afridi et al. reported statistically significant reduction in aura severity (and, thus, theoretical control of cortical spreading depression with subsequent clinical improvement) in eighteen patients with migraine after 25mg dose of IN ketamine.6 We did not report reduction in aura severity, but we did note statistically significant clinical improvement in migraine pain. Specifically, pain scores were significantly reduced in approximately 73.5% of our patient population. Our results, in combination with current literature, supports the efficacy of ketamine as a novel migraine therapeutic option targeting glutamatergic inhibition via NMDA-receptor antagonism.
13
Of note, some patients could confound our results. One patient (classified as a responder due to the resolution of migraine) presented with simultaneous migraine and hand/foot pain. The migraine subsided completely with IN ketamine, but the hand/food pain persisted. This resulted in pain scores with no change from admission to discharge despite migraine resolution. A second patient the patient was initially treated in the ED with IN ketamine and had complete resolution of the migraine at the end of the treatment course. However, the parent refused discharge and was subsequently admitted.
IN ketamine’s place in abortive migraine therapy is still undefined. Current pediatric recommendations generally indicate DHE as the standard of care. Our findings on migraine pain reduction present a valid argument to consider incorporation of IN ketamine into abortive migraine therapy regimens, especially bearing in mind the similarity to Linder et al.’s results and recommendations with IV DHE in pediatric patients. Linder et al. described excellent treatment response in 24 (80%) patients utilizing DHE. Excellent response in this study was defined as >90% reduction in headache intensity or frequency or a >75% reduction in both.22 Using our definition of response, this increased to nearly 90%. A slightly lower, but still clinically significant, amount of patient encounters (73.5%) in our study were classified as responders. It is also important to note the considerable differences in each study’s baseline demographics. Linder et al. performed extensive screenings and exclusions prior to DHE administration.22 In their study, baseline demographics were comparably less refractory to our patient population. In fact, individuals in our study had typically failed multiple standard pharmacologic treatments prior to receiving IN ketamine – the majority of these medications being acetaminophen, antihistamines, antidepressants, DHE, dopamine receptor antagonists, fluid/hydration, NSAIDs, and/or triptans. Linder’s less refractory patient population could have promoted their slightly higher response rate. 14
No IN ketamine dose limit or optimized regimen has been determined. While this study was not designed to do so, efficacy does not appear to correlate to higher doses. Indicators may hint at individual response versus non-response. Significant differences in pain scores between responders and non-responders were noted at each dose. Non-responders appeared to have a small initial pain score reduction on dose one, but subsequent doses resulted in a plateau in pain response. The paradoxical initial decrease cannot be ruled out as potential placebo effect. Conversely, responders appeared to have mean pain reduction on each subsequently administered dose (Figure 2). This difference is useful to note when taken into account with the significant difference in doses administered between groups. It is reasonable to deduce that if a patient is going to respond, they will do so by the 5th dose, and the majority will likely respond by doses 2 and 3 (60% and 76%, respectively, in the present study). Further studies with precise dosing protocols and controls are warranted to truly examine the optimal number of doses and likely time to response.
Notably, repeat courses greater than 72 hours apart do not appear to correlate to tolerance or patterns of abuse. Patients receiving two or more separate IN ketamine courses were excluded from primary analysis, but data was collected to assess subsequent responses for tolerance and potential patterns for abuse. Two patients returned for subsequent doses – each treatment course separated by nearly 4 weeks. One individual received three different courses of IN ketamine with excellent response on courses one and two. It was only on the third occurrence that the individual did not respond to IN ketamine. No definitive description could be provided by these scenarios, but anecdotally, patients appear to respond despite previous doses.
15
Other considerations with migraine treatment are rebound headaches. Zitek, et al. may provide some insight into extended efficacy of ketamine after the patient is discharged home.23 In their study, patients received either prochlorperazine with diphenhydramine or ketamine with ondansetron. At a 24 to 48 hour follow-up, they noted 6/20 (30%) of patients who received prochlorperazine reported a headache, and 9/18 (50%) of patients who received ketamine reported headache – a difference of 20% (95% CI -10.6% to 50.6%).23 While our present study was unable to assess for rebound headaches due to availability of data, we did not record any instance of readmission. Data was not available for readmissions to different facilities, so this may limit proper assessment of true readmission rates. However, it is promising that there were not statistically significant differences in readmission rates to our facility between responders and non-responders.
The avoidance of admission seen with IN ketamine administration in the ED (77.3%) in this present study is potentially advantageous – both fiscally and clinically. Typically, patients are admitted for subsequent DHE dosing if one dose in the ED does not suffice and remain admitted until the migraine resolves. This admission can take several days and involve several dose changes. IN ketamine provides first-tier therapy alternative before resorting to admission. Additionally, in patients whom IN ketamine was initiated in the inpatient setting, pain resolution was sustained long enough to deem the patient stable for discharge. This may ultimately reduce inpatient length of stay in contrast to repeated doses needed for DHE, valproic acid, or other commonly utilized migraine therapies. It is noteworthy to briefly comment on the ED to inpatient admission rate, though. Current literature reports admission rates from the ED to be approximately 7%.24,25 Our ED to inpatient admission rate appeared to be much more frequent (~22.7%); however, our study did not include patients who responded to lower tier treatments (i.e. fluid boluses, dopamine receptor antagonists, NSAIDs) into the total admission calculation 16
whereas previous literature encompassed all potential treatment options. Because a large portion of responders to other therapies were not included in the study, the ED to inpatient admission rate at the present institution was likely much lower than reported. Clinicians should relate our results to their own practice appropriately, but the potential efficacy of IN ketamine should not necessarily be discounted.
Psychotropic, psychedelic, cardiovascular, and hepatic effects have been noted with long term and higher doses of ketamine.9,26,27 Concern for these potential sequelae were largely quelled with the acute, subanesthetic regimen utilized in the present study. Side effects seen were similar to but fewer in number than those reported in current literature. Andolfatto et al. reported mild and transient episodes of dizziness (53%), feeling of unreality (35%), nausea (10%), mood change (8%), and changes in hearing (1%) in adult and pediatric patients (n=40) receiving comparatively higher doses (0.5-0.75 mg/kg/dose) to our study.11 Patients in our study also experienced dizziness (5.6%, n=2/36), dysphoria (8.3%, n=3/36) , and nausea (2.8%, N=1/36), but at much lower rates. Etchison et al. also reported their safe experience with low-dose IV ketamine versus placebo.28 Ketamine, unsurprisingly, had statistically significantly higher Side Effects Rating Scale for Dissociative Anesthetics (SERSDA) scores for fatigue and generalized discomfort compared to placebo; otherwise, all other SERDA score differences were not statistically significant.28 Development of tolerance and patterns of abuse are additional common concerns with ketamine utilization. No patient in the present study appeared to develop either of these for the duration of the study. Caution and more robust studies are still warranted as the present study examines a relatively small cohort over a short duration and does not follow these patients longitudinally. In this particular study, though, ketamine – especially in low doses – appears to be a reasonably safe treatment option with low risk for dependence, even when
17
given after multiple other pharmacologic agents. Monitoring is still encouraged and supported by these results.
IN ketamine offers a major benefit over current traditional migraine protocols: no need for IV access. Current traditional migraine protocols not only require IV access, but may require approximately 1 to 2 hours for one course, and often include multiple doses of fluids, NSAIDs, diphenhydramine, dopamine receptor antagonists, DHE, and/or various other therapeutic alternatives. In contrast, a full course of IN ketamine may be administered in under an hour and requires no IV access nor premedication. These reduce risk of infection, medication exposure, and side effects, decrease time to potential reduction of pain, and expedite readiness for discharge. Protocols utilizing DHE carry several risks (i.e. dystonia, extreme nausea, hypertension, and injection site reactions) and cannot be initiated until at least 24 hours after a triptan has been administered. These risks and limitations are avoided with IN ketamine. Superiority or noninferiority to current standards of care cannot be discerned with current results, but defining IN ketamine as a first tier agent alternative to DHE should not be ruled out, especially considering the aforementioned benefits.
To date, this is one of the largest studies examining IN ketamine for abortive migraine treatment and is the only report of IN ketamine in pediatric patients for abortive migraine treatment. This is the primary analysis, and this data has not previously been published in any form. The retrospective nature (i.e. limited or no depression score records; inability to standardize; no true head to head comparison with other therapeutic options) of this study is limiting. Despite these shortcomings, our study provides meaningful insight on a previously unreported yet seemingly viable and effective therapeutic regimen for a pediatric migraineur population that has limited treatment options. 18
Future studies to examine most effective regimen as well as sequence within current guideline recommendations are warranted. Head-to-head comparison with current standards of care, such as triptans and DHE, would further delineate IN ketamine’s true place within the abortive migraine treatment pathway. For instance, a randomized, prospective head-to-head comparison of DHE and IN ketamine in patients presenting to an ED for abortive migraine therapy would be especially useful. Alternative designs could include patients presenting to an ED for abortive migraine therapy; those with a contraindication to DHE would be assigned to IN ketamine while the remainder would receive IV DHE as usual. Efficacy could then be more accurately compared in both designs. Additional studies of merit include examining long term effects such as depression scores, psychological side effects, tolerance, instances of rebound migraines, and propensity toward patterns of abuse given ketamine’s social stigma.
Practitioners should consider integration of IN ketamine into abortive migraine therapy algorithms. Our experience has promising outcomes in both pain relief and minimization of unwanted, secondary effects. Pediatric migraineurs now have multiple, viable treatment options, and IN ketamine – defined by its potential efficacy, safety, quick onset, and non-invasive nature – provides one that is particularly desirable.
Acknowledgements: Kimberly Tobin, PharmD; Dani Ball, PharmD, BCPPS Author Contributions: AT contributed to design, implementation, data collection, data analysis, interpretation, and created the first draft of the manuscript. SS contributed to design, data analysis, interpretation, and provided meaningful feedback on subsequent versions of this work. EM and MSP contributed to design, data analysis, interpretation, and ongoing edits to the work. 19
BR contributed to design, data clarification, data analysis, interpretation, and ongoing edits to the work. Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Ethical Approval: Approval and a waiver of informed consent was granted by the Cook Children’s Health Care System Institutional Review Board (IRB # 2017-050)
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