Pain Profiles: Prochlorperazine versus Ketamine for Headache

Written by: David Cisewski, MD (@PainProfiles – EM Resident Physician, Icahn School of Medicine at Mount Sinai) // Edited by: Manpreet Singh, MD (@MPrizzleER), Alex Koyfman, MD (@EMHighAK), and Brit Long, MD (@long_brit)

Today’s post in the Pain Profiles series by Dr. David Cisewski evaluates the intranasal route for analgesics.

A Comparison of Headache Treatment in the Emergency Department: Prochlorperazine Versus Ketamine

Zitek T, Gates M, Pitotti C, Bartlett A, Patel J, Rahbar A, et al. A Comparison of Headache Treatment in the Emergency Department: Prochlorperazine Versus Ketamine. Ann Emerg Med. 2018;71(3):369-77 e1. (link)

One-Liner

Combination prochlorperazine/ diphenhydramine offers more pain relief and patient satisfaction than ketamine/ ondansetron for the treatment of acute headaches in the ED.

Study Characteristics

• Clinical question: Is the combination ketamine/ondansetron more effective than prochlorperazine/diphenhydramine at acute headache relief in the ED?
• Design: Multicenter, prospective, double-blind, randomized, controlled trial.
• Setting: A country (tertiary) and a military hospital in Las Vegas, NV.
• Patient/Population: Convenience sampling (2pm – 2am) of 54 patients, age 18-65 years old with acute (benign) headache, afebrile, normotensive (DBP<104), with a normal neurologic exam. Exclusions included breastfeeding, meningeal signs, signs of acute glaucoma, head trauma/LP within last 2 weeks, history IIH, schizophrenic or bipolar, weight >140kg, or received pain medication prior to enrollment.
• Intervention: Patients randomized to received either prochlorperazine 10 mg IV + diphenhydramine 25 mg IV or ketamine 0.3 mg/kg + ondansetron 4 mg IV; both ketamine and prochlorperazine given after diphenhydramine/ ondansetron and pushed over 2 min. Both groups also received 500cc NS bolus following treatment regimen. Primary outcome measured was difference in absolute pain score (VAS) at 60 minutes.  Secondary outcomes included adverse effects (nausea, vomiting, subjective restlessness, headache) and 24-hour follow up call for treatment satisfaction score (0 to 10) and headache relief.
• Outcome: Of the 54 patients enrolled in the study (29 prochlorperazine; 25 ketamine), 2 ketamine patients withdrew for complaints of dysphoria while 1 prochlorperazine withdrew for akathisia. 60 minute VAS reduction (primary outcome) was 64 mm in the prochlorperazine group (95% CI: 53-75) versus 44 mm in the ketamine group (95% CI: 30-57) with a statistically significant difference of 20 mm (95% CI: 3-37mm). Prochlorperazine showed superiority at 45 minutes but both were equally efficacious at 15 and 30 minute intervals. Both groups showed equal rates of nausea/vomit, requirement for rescue medications, degree of restlessness.  24 hour follow up showed a statistically significant satisfaction rating of 8.3/10 for prochlorperazine and 4.9/10 for ketamine (difference of 3.4; 95% CI: 1.2-5.6).
• Conclusion: Combination prochlorperazine/ diphenhydramine offers more pain relief and patient satisfaction than ketamine/ ondansetron for the treatment of acute headaches in the ED

Quality Assessment

This was a  multicenter, prospective, double-blind, randomized, controlled trial powered to detect a difference of 25 mm between groups.  This was a diverse group of patients presenting to an emergency department, consistent with average population presenting with benign headache.

Although this was a blinded RCT, it was limited by the known side effects of ketamine (dysphoria, nystagmus, confusion).  The study was discontinued prior to completing the anticipated 70 patient enrollmentafter several providers expressed concerned about dysphoria effects, suspecting that ketamine was the cause and a potential concern to patient safety (unblinded).  An interim analysis was conducted and after finding strong superiority of prochlorperazine over ketamine, the study was discontinued.  In addition, approximatelyone-fourth of the patients were lost to followup between the 24 to 48 hour follow up, limiting the results of the follow up correspondence data.

Results of comparison between prochlorperazine and ketamine may have been confounded by the additive medication.  The addition of diphenhydramine with prochlorperazine was for prevention of akathisia as a known side effect of dopamine antagonists while ondansetron was given with ketamine to prevent nausea associated with headaches.  Ondansetron is, however, know to cause headaches, possibly limiting the improvement in headache relief shown from ketamine alone.

The Upshot

Headaches continue be a major presenting chief complaint in the ED (Friedman, 2008).  Though many practitioners use prochlorperazine as their first-choice in acute headache treatment, research has continuously demonstrated insufficient headache relief with up to ⅓ of patients having their headache unresolved at discharge (Friedman, 2008).  While some reach for redosing or opioid alternatives, the increasing prevalence of subdissociative dose ketamine (SDK) for analgesia in the ED has lead many to consider it as a viable headache treatment alternative.  Zitek, et al sought to identify the feasibility of ketamine use in this study.

This study should be commended for breaking ground in ketamine use for benign headache relief in the ED and offering us a foundation of research to advance from.  Though ketamine has demonstrated a wide range of analgesic uses, this study does not promote it’s use for headache relief in the ED.  As the efficacy and safety profile of ketamine are optimized, further studies will be necessary to improve our understanding of its role in headache relief.

*New to the Pain Profiles journal club positing is expert consensus for the emergency medicine pain management specialist, Dr. Sergey Motov:

Subdissociative-dose Ketamine for HA in the ED: Not ready for prime time.

Administration of sub-dissociative dose ketamine (SDK) at 0.3 mg/kg over 2 minutes in combination with ondansetron provided less analgesia at 60 minutes (primary outcome of the study) than combination of prochlorperazine and diphenhydramine, resulted in greater need for rescue analgesia, and was associated with lower satisfaction rates. But, upon a much closer look at the results, several interesting findings deserve a very brief discussion.

The intravenous push dose of SDK (over 2 min) resulted in a much better analgesia at 15 minutes than prochlorperazine (change by 40 mm vs. 27 mm) but lesser pain relief at 30,45, and 60 min due to the very short-lived analgesic effect. However, it is plausible to achieve longer lasting and greater analgesic response of SDK by giving it as a short-infusion over 15 minutes. This IVP route resulted in earlier termination of the study (due to dysphoria) without achieving predetermined sample size, and subsequently, statistically enough power to show statically important difference at any pre-specified time periods with respect to analgesia between two groups. Similarly, higher percentage of patients requiring rescue analgesia and suffering from nausea are the consequences of IVP route.

It is unfortunate that authors did not use Side Effect Rating Scale for Dissociative Anesthetics (SERSDA)*to measure unique to ketamine psychoperceptual side effects. Therefore, restlessness and anxiety that were measured and compared between two groups in the study are of limited clinical importance when discussing side effects of ketamine. Finally, from practical perspective, neither prochlorperazine or SDK should be given IVP: it leads to higher rates of akathisias for former and psychoperceptual side effects for latter.

SDK is not a first line analgesic modality for primary headache (tension, migraine) in the ED, probably not even a second. But, it should not be labeled as a useless analgesics modality. Its use should be reserved for patients with multi-drug resistant headache or chronic intractable headache where NMDA/glutamate receptor predominates which is the target of ketamine.

– Dr. Sergey Motov

*SERSDA isa measure of  the severity of nine adverse effects based on a five point scoring system from “0” (adverse effect absent) to “4” (adverse effect is very bothersome).  First described by Eide, 1986 , SERSDA and has since evolved to include the following 9 variables: fatigue, dizziness, headache, feeling of unreality, reduced visual acuity, changes in hearing, mood changes, generalized discomfort, and hallucinations.

References/Further Reading:

• Ben Friedman, MD on headache management from painandpsa.org Emergency Department Management of Acute Headache
• Brit Long, MD on headache management from emDocs.net emDocs Cases: Headache Management in the ED
• Recurrence of primary headache disorders after emergency department discharge: frequency and predictors of poor pain and functional outcomes. Friedman BW, Hochberg ML, Esses D, et al.. Ann Emerg Med. 2008;52:696-704.
• A prospective randomized, double-dummy trial comparing IV push low dose ketamine to short infusion of low dose ketamine for treatment of pain in the ED. Motov S, Mai M, Pushkar I, Likourezos A, Drapkin J, Yasavolian M, et al. Am J Emerg Med. 2017;35(8):1095-100.\