Clinical trial NCT03951649
Conditions: Headache Pregnancy Related Occipital Nerve Block
Keywords: headache Pregnancy Acute treatment Emergency department Occipital nerve block
Sponsor: University of Alabama at Birmingham
Start date: 2020-02-10; Completion date: 2022-12-31
Enrollment: 62 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an open label randomized controlled trial evaluating response to bupivacaine occipital nerve block compared to Tylenol/Caffeine cocktail in treatment of pregnant patients seeking care of headache.

Detailed description:
This is an open label randomized controlled trial. Women who present to the MEU with headache will be assessed by trained nurse practitioners and/or OB/GYN residents. If the woman meets criteria for the study she will be enrolled by an MEU provider doing the primary assessment.

See Figure 1 for the flow diagram depicting the patient's course through MEU. If eligible for inclusion, women will be randomly assigned to ONB or headache cocktail. Randomization will occur at time of enrollment. Prior to headache treatment 10-point visual/verbal rating scale (VRS) will be obtained. Treatment time is defined as time the patient takes the medication or the time that the needle is inserted into the greater occipital notch. At 60 min after treatment VRS will again be obtained by nursing staff or primary provider. If headache pain is resolved, defined as a VRS 0, the patient will be discharged to home (at the discretion of the managing team providing there are no other indications for further observation or admission). If pain continues to be present VRS will again be assessed at 120 min after treatment. If pain is not improved to mild range, defined as a VRS ≤ 3, or resolved, crossover treatment will be given. VRS will be obtained at 60 min after cross over treatment; if pain is resolved patient will be discharge to home. If pain continues to be present VRS will be obtained at 120 min after cross over treatment. If pain is not improved to mild pain or resolved; second line treatment of Promethazine 25mg/Benadryl 25mg will be given. VRS will again be obtained 60 min after second line treatment. If pain is not improved to mild pain (VRS ≤3) or resolved neurology consult will be considered. If at any point during treatment the patient develops new neurological symptoms study protocol will be stopped and neurology will be consulted.

Patients will be called 7 days after discharge to access short term outcomes (headache frequency since MEU visit, injection site complications, and satisfaction with treatment.) Patients will again be called at 28 days and a chart abstraction will be done to access for long term outcomes (recurrent presentation for headache to the MEU, maternal complications including preeclampsia, or fetal complications).

Arms: arm 1: 1. Trained OB/GYN providers will perform a physical exam to access location of occipital nerve injection based on palpation of bony landmarks.
2. Site of injection will be cleaned with an alcohol swab.
3. 5cc of 0.5% bupivacaine will be injected into both right and left occipital nerves using a 2.5 inch 25 gauge needle. The needle will be changed between injecting sites.
4. After injection is completed sterile gauze will be held on injection sites for 2-3 min or until bleeding is resolved. arm 2: Acetaminophen 650mg PO and Caffeine 100mg PO (both Level A treatments for acute headache)
Interventions: intervention 1: Occipital Nerve Block
Intervention descriptions: intervention 1: This is an open label randomized controlled trial evaluating response to bupivacaine occipital nerve block compared to Tylenol/Caffeine cocktail in treatment of pregnant patients seeking care of headache.

Protocol documents:
Prot_SAP_000.pdf: 
1 
 
 
 
Acute headache treatment in pregnancy: 
Occipital Nerve Block compared to Acetaminophen/caffeine PO  
A Randomized Controlled Trial 
(ON ACT  TRIAL) 
 
 
Protocol 
 
 
 
April 15, 2019 
Version 1 
 
 
 


2 
 
Protocol Table of Contents 
1 
Introduction 
 
1.1 Study Abstract 
 
1.2 Primary Hypothesis 
 
1.3 Secondary Hypotheses 
 
1.4 Purpose of the Study Protocol 
2 
Background 
 
2.1 Introduction 
 
2.2 Current Recommendations for treatment of acute headache in pregnancy 
 
2.3 Safety and efficacy of occipital nerve blocks 
 
2.4 Use of occipital nerve block in pregnancy 
 
2.5 Rationale for a Clinical Trial 
 
2.6 Innovation 
 
3 
Study Design 
 
3.1 Primary Research Question 
 
3.2 Secondary Research Aims 
 
3.3 Design Summary 
 
3.4 Study Population and Eligibility Criteria 
 
 
3.4.a Inclusion Criteria 
 
 
3.4.b Exclusion Criteria 
 
3.5 Study Groups 
 
 
 
3.5.a All groups 
 
 
3.5.b Treatment group 
 
 
3.5.c Control group 
 
3.6 Informed Consent 
 
4 
Provider Training 
 
4.1 Procedure Education 
 
4.2 Procedure Technique 
 
5  
Study Procedures 
 
5.1 Screening for Eligibility and Consent 
 
5.2 Randomization 
 
5.3 Patient Flow 
 
5.4 Participant Follow-up 
 
5.5 Adverse Event Reporting 
 
5.6 Study Outcome Measures and Ascertainment 
 
 
5.6.1 Primary Outcome 
 
 
5.6.2 Secondary Outcomes 
 
 
5.6.3 Data Collection and Data Management 
 
 
5.6.4 Follow-up and Outcome Ascertainment Periods 
 
5.7 Telephone script 
 
 
5.7.1: Telephone script at 7 days 
 
 
5.7.2: Telephone script at 28 days  


3 
 
 
6  
Statistical Considerations 
 
6.1 Sample Size for Primary Outcome 
 
6.2 Power for Other Outcomes 
 
6.3 Analysis Plan 
 
 
6.3.1 Primary Analysis 
 
 
6.3.2 Secondary Analysis 
 
6.4 Interim Monitoring 
7  
Future Studies 
8  
References 
9 
Tables and Figures 
Table 1. Inclusion and Exclusion Criteria 
Table 2. Outline of data to be collected 
Table 3. Sample Size  
Table 4. Enrollment time  
 
Figure 1: Occipital nerve block injection site 
Figure 2. Flow of Patients through Study  
Figure 3.  Visual pain scale to be used 
 
 


4 
 
  
Study Title: Acute headache treatment in pregnancy: Occipital Nerve Block compared to 
Acetaminophen/caffeine PO, A Randomized Controlled Trial (ACT ON Trial) 
 
 
Author: Elisa T. Bushman, MD 
Mentor: Rachel Sinkey, MD  
Neurology: Khurram Bashir, MD 
   
1. Introduction 
 
1.1 Study Abstract 
 
Headache is a common complaint in the reproductive population with 16% of women suffering from 
migraine and 88% from tension headache. In the University of Alabama Birmingham (UAB) Maternal 
Emergency Unit (MEU) (analogous to obstetric triage units at other centers), 19-26 patients from 
September-November 2018 presented monthly with the chief complaint of headache. During 
pregnancy the treatment of headache is delayed due to concern for potential fetal exposure limiting 
treatment and appropriate workup. Delaying treatment places women at increased risk for worsening 
of headache disorders and developing more refractory headaches. Improving the treatment of 
headaches has both the potential to improve patient care and satisfaction, and to reduce progression of 
headache disorders. 
 
Occipital nerve blocks (ONB) are a well-established treatment for tension and migraine headaches 
with both abortive and prophylactic treatment benefits. The use in pregnancy currently is limited to 
expert opinion and retrospective studies which show efficacy and safety in the pregnant population in 
the setting of refractory headache.  A MEDLINE review using search terms “occipital nerve block” and 
“pregnancy” yielded 5 results, confirming that there are no randomized trials evaluating ONB in 
pregnancy. Furthermore, clinicaltrials.gov has no registered trials on the topic of occipital nerve block 
and pregnancy as of March 2019.  
 
In light of the paucity of data, we propose a single center open label randomized controlled trial to 
test the central hypothesis that use of occipital nerve block results in greater resolution of pain score 
when compared to Acetaminophen/ Caffeine cocktail for treatment of headache in pregnancy. By 
expanding the use of evidence-based treatment options for headache in pregnancy, our objective is to 
provide this at risk population with improved access to treatment. To our knowledge, this study will be 
the first randomized control trial addressing the use of occipital nerve block in pregnancy. 
 
 
1.2 Primary Hypothesis 
 
Bupivacaine occipital nerve block as compared to Acetaminophen/Caffeine PO cocktail results in a 
greater proportion of pregnant women with response to treatment, defined as resolution or headache 
or improvement to mild severity (VSR ≤3) at 1 hour after treatment.  
 
1.3 Secondary Hypotheses 
Compared to women receiving the PO cocktail treatment, women who receive ONB will:  


5 
 
a) Have improved headache pain at 2 hours following treatment 
b) Have a shortened interval to response to treatment  
c) Have improved satisfaction with treatment 
d) Have decreased headache frequency for the 7 days following treatment  
e) Experience no difference in the development of hypertensive disease of pregnancy at 7 days 
following treatment  
f) Have less utilization of crossover treatment  
g) have no difference in the development of hypertensive disease of pregnancy at 28 days 
following treatment  
h) Have decreased utilization of MEU services in the next 28 days  
i) 
Have a greater improvement in pain scores 
 
1.4 Purpose of the Study Protocol 
 
The purpose of our study is to determine if ONB is a beneficial first line treatment of acute headache in 
pregnancy.  
 
 
 


6 
 
2. Background 
 
2.1 Introduction 
 
Headache is a common complaint in the reproductive population. Primary headache disorders include 
migraine, cluster, and tension headache. Of reproductive age women, 1/6 suffer from migraine and 88% 
meet criteria for tension headache at some point in their life.1,2  Despite an anticipated improvement in 
primary headache disorders with pregnancy, primary headache disorders can initially present, worsen, 
or be diagnosed during pregnancy.3 The diagnosis and treatment of acute headache in pregnancy is of 
great importance as it can dictate delivery and early maternal/fetal interventions.  
 
During pregnancy the treatment of headache is made more difficult due to an increase in secondary 
headaches, such as pre-eclampsia, and concern for potential fetal exposure limiting treatment.4  As a 
result treatment of headache disorders is delayed during pregnancy.5 Delaying treatment of headache 
disorders places women at increased risk for worsening of primary headache disorders and developing 
more refractory headaches.6  The improved treatment of headache has both the potential to improve 
patient care, satisfaction, and disease progression of headache disorders. 
 
Occipital nerve blocks (ONB) are a well-established treatment for tension and migraine headache in 
the non-pregnant population with both abortive and prophylactic treatment benefits.7-13 ONBs are a 
safe procedure that involves a subcutaneous injection of local anesthetic with or without a steroid 
component bilaterally into the area around the occipital nerves.14 The local anesthetic used is typically 
lidocaine or bupivacaine both of which are routinely used with epidural placement. The use in 
pregnancy currently is limited to expert opinion and retrospective studies which suggest efficacy and 
safety in the pregnant population.15  Complications of occipital nerve blocks are limited to rare injection 
site infections.  A MEDLINE review using search terms “occipital nerve block” and “pregnancy” yielded 5 
results, confirming that there are no randomized trials evaluating ONB in pregnancy. Furthermore, 
clinicaltrials.gov has no registered trials on the topic of occipital nerve block and pregnancy. By 
expanding the use of evidence-based treatment options for headache in pregnancy this at risk 
population may have improved access to treatment. 
 
Figure 1: Site of injection of occipital nerve block13 
 
 


7 
 
2.2 Current Recommendations for treatment of acute headache in pregnancy 
 
There are many good treatment options for acute headache in pregnancy however these treatments are 
underutilized due to provider discomfort. This innate discomfort is likely due to a lack of evidence based 
treatment protocols for headache in pregnancy. As a result first line treatment varies widely by 
institution and provider.  
 
There is level A evidence for the use of acetaminophen, acetaminophen/aspirin/caffeine (Excedrin 
Migraine®), and butorphanol for treatment of acute headache that are all safe for use during 
pregnancy.16,17 Due to the concern for blood thinning and a theoretical risk of closure of the fetal ductus 
arteriosus, regular-dose aspirin is avoided by many providers in the 3rd trimester.18 As a result many 
providers favor the use of acetaminophen/butalbital/caffeine (Fioricet®) despite there being no Level A 
or Level B evidence for the use of butalbital containing medications for treatment of headache. Despite 
butorphanol being a Level A treatment for acute headache use in pregnancy is again limited by provider 
comfort. Ketoralac, naproxen and ibuprofen are also FDA level A and can be safely used prior to 28 
weeks for 48-72 hours. However, the potential risk of premature closure of the ductus arteriosus, 
platelet dysfunction, and/or fetal and maternal renal dysfunction limit NSAIDS use for treatment of 
headache in pregnancy, particularly in the third trimester.17  
 
Level B medications that can be used for the treatment of acute headache in pregnancy are the 
dopamine blockers: chlorpromazine, promethazine, metoclopramide, and prochloperazine.17 The exact 
mechanism of dopamine blockade on headache is unknown but is felt to be safe in pregnancy and have 
the added benefit of treatment of nausea. There is also Level B evidence for the use of Codeine in 
combination with acetaminophen and tramadol in combination with acetaminophen, but these are used 
more rarely due to increasing awareness of their potential for maternal opioid use disorder and the 
potential for neonatal withdrawal syndrome with chronic maternal opioid use. 
 
Despite headache being a common complaint in pregnancy there is no obstetric or neurologic society 
that has standardized recommendations for treatment of headache in pregnancy leaving treatment 
provider dependent.    
 
2.3 Safety and efficacy of occipital nerve blocks 
 
Injection of local anesthesia into the greater or lesser occipital nerve, known as occipital nerve block 
(ONB), is an acute and prophylactic treatment of headache commonly used outside of pregnancy. Five – 
ten cc of local anesthetic with or without steroid is injected into the greater occipital nerve and/or lesser 
occipital nerve every 6-9 weeks as desired for prophylactic benefit. ONB has been studied extensively in 
both randomized controlled trails and prospective cohort studies. Randomized controlled trials show 
therapeutic benefit with clinically significant reduction in headache (HA) days in the 1st week, and 2 and 
3 months following ONB.7,9 Retrospective studies has shown benefit of occipital nerve block in all 
primary headache disorders (cluster, migraine and tension).8 While reducing the number of headache 
days ONB has also been shown to decreased use of oral medication consumption over the month 
following injection.10,11 Due to the acute benefit of ONB the use in emergency department settings is 
becoming an area of increasing interest. Current evidence shows that the use of ONB in acute care 
settings is safe with risk of complication being similar to that of any subcutaneous injection.14 Response 
of acute headache to ONB ranges from a 50% pain reduction in pain to 90% resolution at 45 minutes 
after treatment.19,20  
 


8 
 
2.4 Use of occipital nerve block in pregnancy 
 
Although use of ONB has not been studied extensively in pregnancy a case series has been published 
with a population of 13 pregnancies who failed oral and IV treatment of migraine. Of these women, 38% 
suffered from chronic migraines with 51% suffering from status migrainosis (migraine lasting >72hrs) at 
the time of injection. Eleven patients had acute pain relief and resolution. Two patients had no pain 
relief and went on to be diagnosed with preeclampsia and no patients suffered from minor or major 
complications.15  
 
The American Headache Society distributed a member survey 2010 with 161 responses questioning the 
use of ONB in pregnancy. Greater than one half of members surveyed preformed ONB in pregnancy and 
felt it was safe. The majority of practitioners usually waited until 2nd trimester to give injections and 
used lidocaine only although there is no evidence that ONB in the first trimester or use of other types of 
local anesthetic is unsafe.13  
 
2.5 Rationale for a Clinical Trial 
 
Few studies exist which have examined the treatment of acute headache in pregnancy. Treatment of 
headache in pregnancy is currently based on extrapolated treatment of headache in the non-pregnant 
population. Specifically, no published data exists involving the use of ONB in the acute setting.  Our 
study would provide evidence on the potential benefits of ONB for treatment of headache in pregnancy 
providing an additional treatment tool in this at risk population.    
 
2.6 Innovation 
 
There is a paucity of data regarding treatment of headache in pregnancy with most research 
addressing the natural course of headache in pregnancy rather than treatment of headache in 
pregnancy. 21,22 There is scant literature addressing the use of ONB in an emergency department setting 
but the few published studies are promising showing efficacy and safety. 14,15  A MEDLINE review using 
search terms “occipital nerve block” and “pregnancy” yielded 5 results, confirming that there are no 
randomized trials evaluating ONB in pregnancy. Furthermore, clinicaltrials.gov has zero registered trials 
on the topic of occipital nerve block and pregnancy. This innovative randomized controlled trail will 
expand the use of evidence-based treatment options for headache in pregnancy leading to improved 
access to evidence based treatment of acute and chronic headache in pregnancy. 
 
3. Study Design 
 
This is an open label randomized controlled trial evaluating response to bupivacaine occipital nerve 
block compared to Tylenol/Caffeine cocktail in treatment of pregnant patients seeking headache 
treatment. 
 
3.1 Primary Research Question: Is occipital nerve block more efficacious than Tylenol/ Caffeine cocktail 
in the treatment of headache in pregnancy?  Benefit of occipital nerve block will be defined as a 
resolution or improvement of headache pain to mild range (VRS ≤ 3) at 1 hours by visual/verbal rating 
score (VRS).  
 
3.2 Secondary Research Aims:  
a) To assess the difference in response to treatment at 2 hours following treatment.  


9 
 
b) To assess the difference in time to resolution of pain after treatment of acute headache 
between groups.  
c) To assess patient satisfaction with treatment at time of discharge and at 7 days.  
d) To assess headache free duration within 7 days after treatment. 
e) To assess the development of hypertensive disease of pregnancy without 7 days after 
treatment.  
f) To assess the need for crossover treatment.  
g) To assess development of hypertensive disease of pregnancy within 28 days of treatment.  
h) To assess the need of MEU services for treatment of headache within 28 days of treatment.  
i) 
To assess the change in VSR before and after treatment.  
 
3.3 Design Summary: This is an open label randomized controlled trial. Women who present to the MEU 
with headache will be assessed by trained nurse practitioners and/or OB/GYN residents. If the woman 
meets criteria for the study she will be enrolled by an MEU provider doing the primary assessment.  
 
See Figure 2 for the flow diagram depicting the patient’s course through MEU. If eligible for inclusion, 
women will be randomly assigned to ONB or headache cocktail. Randomization will occur at time of 
enrollment. Prior to headache treatment 10-point visual/verbal rating scale (VRS) will be obtained.  
Treatment time is defined as time the patient takes the medication or the time that the needle is 
inserted into the greater occipital notch. At 60 min after treatment VRS will again be obtained by 
nursing staff or primary provider. If headache pain is resolved, defined as a VRS 0, the patient will be 
discharged to home (at the discretion of the managing team provided there are no other indications for 
further observation or admission). If pain continues to be present VRS will again be assessed at 120 min 
after treatment. If pain is not improved to mild range, defined as a VRS ≤ 3, or resolved, crossover 
treatment will be given. VRS will be obtained at 60 min after cross over treatment; if pain is resolved 
patient will be discharge to home. If pain continues to be present VRS will be obtained at 120 min after 
cross over treatment. If pain is not improved to mild pain or resolved; second line treatment of 
Promethazine 25mg/Benadryl 25mg will be given. VRS will again be obtained 60 min after second line 
treatment. If pain is not improved to mild pain (VRS ≤3) or resolved neurology consult will be 
considered. If at any point during treatment the patient develops new neurological symptoms study 
protocol will be stopped and neurology will be consulted.  
 
Patients will be called 7 days after discharge to access short term outcomes (headache frequency since 
MEU visit, injection site complications, and satisfaction with treatment.) Patients will again be called at 
28 days and a chart abstraction will be done to assess long-term outcomes (recurrent presentation for 
headache to the MEU, maternal complications including preeclampsia, or fetal complications). 
 
3.4 Study Population and Eligibility Criteria:  
 
Inclusion criteria:  
a) Women presenting to Maternal Evaluation Unit at UAB hospital 
b) Confirmed live intrauterine pregnancy (previous ultrasound, bedside ultrasound, or fetal 
monitoring) 
c) Complaint of headache  
d) Minimal pain level of 4 on VRS 
 
Exclusion criteria: 
a) Systolic BP >= 140 or diastolic BP>=90 with 1+ protein on urine dip 


10 
 
b) Systolic BP >=160 or diastolic BP>=105 
c) Focal neurological symptoms 
d) Altered level of consciousness defined as not being oriented to person, place, situation, and/or 
year 
e) Complaint of seizure 
f) Known under lying brain abnormality 
g) Fever 
h) Use of >3 grams of acetaminophen in past 24hrs 
i) 
ONB in the past 3 months 
j) 
Reported allergy to study medications (Bupivacaine, acetaminophen, or caffeine) 
 
Table 1. Inclusion and Exclusion Criteria 
Inclusion 
Exclusion 
 
Women presenting to Maternal Evaluation 
Unit at UAB hospital 
 
Pregnancy confirmed on bedside US or with 
fetal monitoring 
 
Complaint of headache  
 
Pain level of ≥4on VRS 
 
BP >140/90 with 1+ protein on urine dip 
 
BP >160/105 
 
Focal neurological symptoms 
 
Altered level of consciousness defined as not 
being oriented to person, place, situation, 
and/or year 
 
Complaint of seizure 
 
Known under lying brain abnormality 
 
Fever 
 
Use of >3g of acetaminophen in past 24hrs 
 
ONB in the past 3 months 
 
Reported allergy to study medications 
(Bupivacaine, acetaminophen, or caffeine) 
 
VRS score <4 
 
No transportation 
 
Non English speaking  
 
3.5 Study Groups:   
 
There will be two intervention groups:  
 
a) Occipital Nerve block Group (Treatment): 8,11 
a. Trained OB/GYN providers will perform a physical exam to access location of occipital 
nerve injection based on palpation of bony landmarks.  
b. Site of injection will be cleaned with an alcohol swab. 
c. 5cc of 0.5% bupivacaine will be injected into both right and left occipital nerves using a 
2.5 inch 25 gauge needle.  The needle will be changed between injecting sites.   
d. After injection is completed sterile gauze will be held on injection sites for 2-3 min or 
until bleeding is resolved.  
b) Oral Tylenol/Caffeine Group (Control):  
a. Tylenol 650mg PO and Caffeine 100mg PO (both Level A treatments for acute 
headache)16,17,23 
 
3.7 Informed Consent 


11 
 
Institutional Review Board (IRB) approved informed consent forms will be presented to the patient, and 
informed consent must be obtained prior to enrolling the patient in this randomized controlled trial. The 
full list of potential risks to the patient and her neonate will be listed in the informed consent. The 
nature and purpose of the study will also be detailed in the informed consent. The patient will be 
provided a copy of the signed informed consent. The informed consent will only be in English, and thus, 
only English-speaking individuals may participate in the study. 
4. Provider Training  
4.1 Procedure Education 
All MEU providers will be trained in ONB prior to initiation of study. Procedure methods used will be 
those recommended by the expert consensus on performance of nerve blocks published by the 
American Headache Society in 2013.13 All teaching will be done in a single 30min session during resident 
didactics. Teaching will be done by a neurology trained provider with extensive experience in ONB. MEU 
providers will practice injections on models with supervision during the teaching session and will be 
signed off on procedural technique at the end of the session. 
4.2 Procedure Technique 
1. Supply Preparation:  
a. 10 cc of 0.5% bupivacaine will be drawn up into a 10 cc syringe using a draw up needle. 
b. A 1.5-2 inch 27 gag needle will be placed on the 10 cc syringe. 
c. A second 1.5-2 inch 27 gag needle will be opened and ready for exchange of needles 
between injection sites.  
d. Two alcohol swabs 
e. Two 2x2 gauze or 2 cotton balls 
2. Positioning: The patient will be positioned in a sitting position leaning forward with forehead 
resting on crossed arms over a table.   
3. Location: Bilateral greater and lesser occipital notches will then be palpated with gloved non 
sterile hands. After boney landmarks have been identified, one finger pressure will be placed on 
a unilateral greater occipital notch. Pressure will then be released. Then, on the same side using 
one finger the lesser occipital notch will be palpated. The patient will be asked which results in 
more pain. Based the patient response the site of greatest pain will be chosen as the site of 
injection. Attention will then be turned to the opposite side and testing will be repeated. After 
bilateral sites of injection has been identified based on physical exam.  Injection site will be 
recorded.     


12 
 
4. Injection: Bilateral sites will be cleaned with an alcohol swab. 5cc of bupivacaine will then be 
injected after the needle has been inserted until boney land mark is hit. If a boney landmark is 
not hit the needle will be withdrawn and inserted superiorly to ensure injection in to supra-ostia 
area. Prior to injection the plunger will be drawing back to assess for vascular structure. If there 
is return of blood the needle we removed and reinserted. The injection will not be given until 
there is no return of blood suggesting vascular penetration. After injection into unilateral 
occipital nerve the needle will be exchanged and 5cc of 0.5% bupivacaine will be injected into 
contralateral site previously identified using the same technique. 
5. Post-injection care: After injections have been completed the patient will hold gauze or cotton 
balls on bilateral injection site for 2-3 mins. The site will then be examined for continued 
bleeding. If bleeding is present pressure will be held until bleeding is resolved.  
5. Study Procedures 
5.1 Screening for Eligibility and Consent 
All patients who present to the MEU will be screened for inclusion in the study. If the patient meets 
eligibility criteria, the MEU provider will present the study, which includes risks, benefits, procedures, 
and alternatives. The informed consent will be signed after all questions have been answered. 
5.2 Randomization 
After the treating provider has consented the patient, she will be randomized. Randomization will occur 
by a predetermined computer-generated block randomization scheme prepared by a study statistician 
with further stratification by trimester to account for anticipated decrease in headache frequency 
through pregnancy. 
5.3 Flow of patients 
All Patients (both treatment and control groups):  
a. Blood pressure and urine assessment will be performed in the MEU 
b. Fetal viability will be confirmed with ultrasound or fetal heart monitoring 
c. Gestational age will be verified by review of early ultrasound of fetal biometry on 
admission 
d. All women with the compliant of headache will have pain accessed with VRS 
e. Brief neurological exam will be done on all patients to access for gross deficits (Strength, 
Sensory, and cranial nerve assessment) 
f. Women meeting inclusion and exclusion criteria will be enrolled by MEU provider 
performing primary assessment 
g. Women will be randomized at time of enrollment 
h. 60 minutes after treatment VRS score will be obtained if headache is resolved patient 
will be discharge to home. If pain is not resolved VRS will be repeated at 120 minutes. If 
pain is mild (VRS ≤ 3) or resolved patient will be discharged to home. If moderate or 
unimproved patient will be given cross over treatment.  


13 
 
i. 
60 minutes after crossover treatment VRS score will be obtained if headache is resolved 
patient will be discharge to home. If pain is not resolved VRS will be repeated at 120 
minutes. If pain is mild or resolved patient will be discharged to home. If moderate or 
unimproved patient will be given second line treatment of Promethazine 
25mg/Benadryl 25mg PO (Level B treatment for headache)17. 
j. 
60 minutes after second line treatment VRS score will be obtained if headache is 
resolved or mild patient will be discharge to home. If pain is not improved neurology 
consult will be placed.    
k. It at any point during study protocol new neurological deficit develops study protocol 
will be stopped and neurology consult will be placed. 


14 
 
Figure 2. Flow of Patients through Study   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Presents to MEU with 
complaint of HA 
BP <140/90 with <1+ 
proteinuria 
Normal Neurological exam 
VRS >4
Screen for study
Randomize  
Obtain consent if eligible
Occipital Nerve Block 
(0.5% bupivacaine SC 5cc 
bilateral occipital nerves) 
Headache Cocktail 
(Acetaminophen 650mg 
PO/Caffeine 200mg PO) 
VRS 60 min after treatment
Discharge to home 
Repeat VRS at 
120min
VRS≤3
VRS≤3 
Discharge to home 
Give cross over treatment  
 VRS>3 
VRS≤3 
Discharge to home 
Repeat VRS at 
120min
VRS>3 
VRS≤3 
VRS 60 min after treatment
VRS>3 
Discharge to home 
Give Second Line treatment  
Discharge to home 
Neurology consult  
VRS≤3 
VRS≤3 
VRS 60 min after treatment
VRS≤3 


15 
 
5.4 Participant Follow-Up 
Patients will be called by investigators at 7 days and 28 days after treatment to access satisfaction with 
treatment. Patients will be asked if on a scale of 1-10 if they would recommend treatment to a friend; 
with 10 being recommended and 1 being advise against. Headache free duration will be assessed at 7 
days and will be record and days headache free following treatment. At 7 days development of local 
injection site reaction will also be assessed.  At 7 and 28 days need for representation for headache 
treatment and development of hypertensive disease of pregnancy will be assessed.  
In addition investigators experienced in abstracting obstetrical outcomes will review the patient’s chart 
at 28 days to assess for recurrent headache, representation for treatment of headache, and 
development of hypertensive disease of pregnancy.   
5.5 Adverse Event Reporting 
A Data Safety Monitoring Board (DSMB) will be formed and consist of three individuals within the 
Division of Maternal-Fetal Medicine and Department of Pediatrics who have no ties to the study design, 
evaluation of results or potential authorship of the manuscript.  The primary purpose of the DSMB will 
be to monitor patient safety. The members of this board will be Brian Smins, Janeen Arbuckle, and 
Rhiannon Reed.  
The purpose of the study is to determine whether ONB is a beneficial treatment for headache in 
pregnancy in an acute care setting. In pregnancy treatment of headache is delayed due to concern for 
fetal exposure and provider experience. As a result headache treatment is not standardized in 
pregnancy and varies widely based on provider comfort and experience. Expanding the use of ONB in 
this population may lead to improved access to treatment.  
Potential risks of ONB are injection site infection, development of hematoma and ecchymosis. The risk 
of infection is the same as any subcutaneous infection. Risk will be minimized by cleaning the injection 
site with alcohol prior to injection. Sterile tips will be used and injecting needs will be changed between 
injections to further minimize risk of injection site infection. To reduce the risk of hematoma and 
ecchymosis pressure will be held on injection site for 2-3 min following injection.    
We define an adverse event as an undesirable experience or outcome occurring in a research 
participant, regardless of whether participation in the research study caused the event to occur.  For 
example, maternal death and/or fetal demise are known risks of pregnancy, and while not known to be 
related to occipital nerve block, would be considered an adverse event if it occurred during the study. All 
serious adverse events will be reported to the DSMB and IRB. A serious adverse event will include the 
following events, if occurring within 28 days of treatment: 
a. Injection site complications:  
a. Infection 
b. Hematoma 
b. Development of hypertensive disease of pregnancy  


16 
 
c. Death 
a. Maternal  
b. Fetal (stillbirth) 
c. Neonatal 
d. Life-threatening event 
e. Prolonged maternal hospitalization >5 days 
f. Any other event not listed that the investigators believe may have been caused by the 
intervention. 
 
5.6 Study Outcome Measures and Ascertainment 
5.6.1 Primary Outcome 
Based on guidelines from the International Headache Society the primary outcome is the portion of 
women who experience resolution of headache or improvement of headache to mild range (VRS ≤ 3) at 
2 hours following treatment with Occipital nerve block as compared to acetaminophen/caffeine 
cocktail.24  
 
5.6.2 Secondary Outcomes 
a. Response to treatment within 2 hours 
b. Need for crossover treatment  
c. Response to cross over treatment at 60 or 120 min 
d. Need for second line treatment 
e. Response to second line treatment at 60 min  
f. Need for neurology consult 
g. Need for admission for treatment of headache 
h. Need for representation for treatment of headache with 28 days 
i. 
Development of hypertensive disease of pregnancy within 28 days  
j. 
Satisfaction with treatment at 7 days  
k. Duration of headache free period at 7 days  
l. 
Development of hypertensive disease of pregnancy within 7 days 
m. Response for headache treatment will be adjusted for by primary headache disorder 
n. Need for neuroimaging within 28 days 
o. Injection site complication (infection, hematoma, and ecchymosis)   
 
5.6.3 Data Collection and Data Management  
 
We will collect data at 7 and 28 days from study participants. Relevant data will be collected initially to 
assess eligibility. Complete baseline information and outcome data will be collected by trained MEU 
providers by direct interview and chart review. The study statistician and the primary investigator will be 
responsible for coordinating the overall data management of the trial. Data management includes: 
development and maintenance of study case report forms and the electronic database, procedures for 


17 
 
data entry, data editing, and compilation; procedures for quality control, data verification, 
confidentiality, and security. Data will be collected and managed with REDCap (Research Electronic Data 
Capture), an established, secure, web-based data capture and management tool developed at 
Vanderbilit University and supported by the bioinformatics team at UAB. Missing data rates and 
patterns will be assessed monthly by the primary investigator, and remedial measures, including re-
abstraction of data and retraining of staff, will be used as needed to minimize missing data. 
 
Figure 3. Visual Pain Scale to be used 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 2. Outline of Data to be Collected 
 
 
Prior To Treatment 
 
o 
Demographics (age, race, 
ethnicity, marital status, 
insurance status) 
o 
Obstetric history (prior 
cesarean, number of 
deliveries) 
o 
5 point headache history 
(family, life, attack, 
general, and medication) 
o 
Maternal BMI 
o 
Gestational age 
o 
Pregnancy comorbidities  
o 
Assessment for 
hypertensive disease of 
pregnancy 
o 
Basic neurological exam  
 
Treatment 
 
After primary treatment 
o 
VRS score at 60 min 
o 
VRS score at 120 min if 
VRS ≥3 at 60 min 
After crossover treatment 
o 
VRS score at 60 min 
o 
VRS score at 120 min if 
VRS ≥3 at 60 min 
After 2nd line treatment  
o 
VRS score at 60 min 
 
o 
Need for admission 
o 
Need for Neurology 
consult  
 
 
7 days Following treatment 
 
Telephone Call:  
o 
Timing to return to 
headache in days 
o 
Satisfaction with 
headache treatment, 
likeliness of 
recommending 
treatment 
o 
Complication of 
hematoma, ecchymosis, 
or site infection 
o 
Need for return to EU 
for treatment of HA 
o 
Development of 
hypertensive disease of 
pregnancy  
o 
Maternal or fetal 
complication 
 
28 days following treatment  
 
Telephone Call:  
o 
Need for return to EU for 
treatment of HA 
o 
Development of 
hypertensive disease of 
pregnancy  
o 
Maternal or fetal 
complication 
Chart Review:  
o 
Need for return to MEU 
for treatment of HA 
o 
Development of 
hypertensive disease of 
pregnancy  
o 
Maternal or fetal 
complication 
 


18 
 
5.6.4 Follow-up and Outcome Ascertainment Periods 
Response to treatment will be ascertained by VRS prior to treatment and again at 60 min after 
treatment and 120 minutes after treatment if headache is not resolved or mild at 60 min. VRS score will 
again be obtained 60 min after crossover treatment and 120 min after crossover treatment if headache 
is not resolved or is mild. If second line treatment is given VRS will be obtained 60 min after crossover 
treatment. Maternal outcomes (e.g. injection site infection or development of pre-eclampsia) are 
delayed outcomes which will require review after discharge. These outcomes will be assessed at 7 and 
28 days after treatment by telephone call and chart review. 
5.7 Telephone scripts:  
5.7.1 Telephone script at 7 days:  
Introduce yourself 
Hello, my name is _________ from the department of maternal fetal medicine at UAB hospital.  
Tell the person why you are calling 
I am calling to follow up on treatment you received for a headache at the UAB Maternity Evaluation 
Unit.  Is now a good time to discuss your treatment?  
If person says “No,” thank the person for her time and ask if there is a better time to call back. 
If person says “Yes,” inform them about use of their private health information (PHI) that will be 
collected during the phone call.  
 
Use the following language: We will be collecting information about you during this phone call. 
You taking part in this phone call is completely voluntary. The information you provide will only 
be seen by researchers at UAB hospital. We try to make sure that the information we collect 
from you is kept private and used only for the headache research study you were enrolled in. If 
you do not agree to continue to phone call, it will not affect your care at UAB Hospital.  
Begin questionnaire 
1. How satisfied were you with the treatment you received? Zero being strongly dissatisfied, 2 
being neutral, and 4 being very satisfied.  
2. How likely are you to recommend the treatment you received to a friend? Zero Very unlikely, 2 
no opinion, 4 very likely 
3. Have you had a return of headache since your treatment? If yes how long was it until your 
headache returned?  
4. If your headache has returned is it the more, the same, or less severe than it was prior to 
treatment?  


19 
 
5. For patients that received ONB: Did you develop any signs of infection or swelling at the site of 
your injection? If so can you describe them to me?  
6. Since your treatment have you represented to any provider (ER, MEU, or clinic) for treatment of 
headache?  
7. Since being treated has your doctor diagnosed you with any blood pressure problems in 
pregnancy such as gestational hypertension or pre-eclampsia?  
8. Since being treated have you developed any new complications in your pregnancy?  
9. Are there any other aspects of your headache treatment you would like to discuss with me?  
Thank the person for participating is the study 
Thank you for taking time to discuss your experience with me and for participating in the study. You will 
be contacted again in 3 weeks to readdress your experience.  
5.7.2 Telephone script at 28 days:   
Introduce yourself 
Hello, my name is _________ from the department of maternal fetal medicine at UAB hospital.  
Tell the person why you are calling 
I am calling to follow up on treatment you received for a headache at the UAB Maternity Evaluation 
Unit.  Is now a good time to discuss your treatment?  
If person says “No,” thank the person for her time and ask if there is a better time to call back. 
If person says “Yes,” inform them about use of their private health information (PHI) that will be 
collected during the phone call.  
Use the following language: We will be collecting information about you during this phone call. 
You taking part in this phone call is completely voluntary. The information you provide will only 
be seen by researchers at UAB hospital. We try to make sure that the information we collect 
from you is kept private and used only for the headache research study you were enrolled in. If 
you do not agree to continue to phone call, it will not affect your care at UAB Hospital.  
Begin questionnaire 
1. How satisfied were you with the treatment you received? Zero being strongly dissatisfied, 2 
being neutral, and 4 being very satisfied.  
2. How likely are you to recommend the treatment you received to a friend? Zero Very unlikely, 2 
no opinion, 4 very likely 


20 
 
3. Since your treatment have you represented to any provider (ER, MEU, or clinic) for treatment of 
headache?  
4. Since being treated has your doctor diagnosed you with any blood pressure problems in 
pregnancy such as gestational hypertension or pre-eclampsia?  
5. Since being treated have you developed any new complications in your pregnancy?  
6. Are there any other aspects of your headache treatment you would like to discuss with me?  
Thank the person for participating is the study 
Thank you for taking time to discuss your experience with me and for participating in the study. You will 
not be contacted further regarding this study.  
6. Statistical Considerations  
6.1 Sample Size for Primary Outcome 
The total sample size is estimated based on the analysis for the primary outcome. From this we estimate 
our ability to detect a difference in secondary outcomes. All sample size and power estimates are based 
on treating a pain improvement as a dichotomous outcome with the endpoint being resolution of pain or 
improvement in pain to mild severity (VRS ≤3). The improvement of headache with acetaminophen 
500mg/Aspirin 500mg/Caffeine 130mg PO is 50% pain reduction to mild headache at 65min.23 Given 
Aspirin is not felt to be a potent anti-headache medication we have assumed the same or similar 
response to Acetaminophen 650mg/Caffeine 100mg PO cocktail to reduce exposure to aspirin given 
theoretical fetal risk of early closure of ductus arteriosus. We anticipate a 58-90% reduction following 
occipital nerve block.19,20 Given recent randomized controlled trails evaluating treatment of acute 
headache with ONB showing a response of 90% at 45 min and retrospective studies evaluating the use 
of ONB in the setting of headache prophylaxis showing a 82% with mild or significant response and 58% 
showing significant response at 1 month, we have chosen an 85% response rate to account for this 
variation in results. We estimate that a total of 62 women (31 ONB and 31 Acetaminophen/Caffeine) will 
be sufficient to detect a difference in headache resolution at 1 hour, with 80% power and a 5% 
significance level.  To account for a 5% loss to follow up, we will aim to enroll 86 women. On average 
there are 750 evaluations in the MEU each month with 19-26 of these patients presenting with the chief 
complaint of headache. Based on a 25% enrollment rate we have calculated it will take 16 months to 
complete enrolment.  
 
 Table 3: Sample Size* 
Headache resolution at 2 hours 
Sample Size per 
Group 
Total Sample 
Size 
ONB 
Acetaminophen/Caffeine 
90%  
50% 
19 
38 
85% 
50% 
28 
56 
80% 
50% 
38 
76 


21 
 
70% 
50% 
93 
186 
60% 
50% 
387 
774 
  *Based upon 80% power and significance of 0.05 
 
Table 4: Enrollment Time  
Enrollment rate per 
month 
Enrollment goal per 
month 
Total study time in 
month 
10% 
2 
31 
25% 
5 
12 
50% 
10 
6.2 
75% 
15 
4.1 
 
6.2 Power for Other Outcomes 
The sample size of 86 for the primary aim will be sufficient to provide 80% power to detect an absolute 
difference of 30% between ONB and acetaminophen/caffeine headache cocktail (odds ratio of 4, risk 
ratio of 1.6) at significance level of 5%.  While this study will not be definitive regarding the potential 
benefits associated with ONB for specific headache disorders when compared to 
acetaminophen/caffeine, it will provide important baseline information to power a future randomized 
study evaluating the benefits of ONB for treatment of specific headache disorder in pregnancy. In 
addition we anticipate we will be underpowered to detect differences between individual components 
concerning prophylactic benefit of ONB.  
 
6.3 Analysis Plan 
Data analyses will adhere closely to those recommended by the International Headache Society 
Guidelines for controlled trial on treatment of acute migraine attacks.24 Analyses will follow the 
intention to treat principle in which participants will be analyzed in the group to which they were 
randomized, regardless of whether or not they received the assigned intervention.25 
 
6.3.1 Primary analysis: Descriptive statistics will characterize the group of individuals recruited and 
investigate comparability of the two groups at baseline. Formal statistical testing will be limited to 
selected baseline characteristics considered to be prognostic factors for the primary outcome such as 
known diagnosis of primary headache disorder and baseline headache severity. The categorical 
prognostic factors will be compared between trial groups by using the Chi-square test of association or 
Fisher’s exact tests as appropriate. The two-group independent t-test and the Mann-Whitney U test, as 
appropriate, will be used to compare quantitative characteristics between the trial groups. 
 
The primary outcome and other categorical secondary outcomes will be compared between 
intervention groups by using the Chi-square test. We will use the Breslow-Day test to assess 
homogeneity of the odds ratios across the gestational age categories.   Multivariable logistic regression 


22 
 
models will be used to estimate treatment effects while adjusting for potential confounders.  
Characteristics that are imbalanced at baseline will be considered as covariates in multivariable models.  
Adjusted odds ratios and 95% confidence intervals will be estimated.  Multivariable modified Poisson 
regression models will be considered to estimated adjusted risk ratios and 95% confidence intervals. 
 
 
6.3.2 Secondary Analysis.  
Secondary outcomes will be evaluated using the approaches for categorical variables described above.  
Quantitative secondary outcomes will be compared using the two-sample t-test or Mann-Whitney U 
tests (as appropriate) as described above.  Multivariable regression models including imbalanced 
baseline characteristics will be explored to determine estimated treatment differences while accounting 
for potential covariates.  Estimated beta coefficients and 95% confidence intervals will be generated. 
6.4 Interim Monitoring 
Given the small sample size we do not plan an interim analysis. The interventions compared in this trial 
are both currently used in clinical obstetric practice and there is no defined standard of care. Therefore, 
no serious or life threatening adverse events are expected. Nonetheless, the following measures will be 
taken to monitor and investigate adverse events: 
1. Independent Data and Safety Monitoring Board (DSMB): We have assembled an independent, 
study-specific DSMB composed of three distinguished individuals Brian Smins, Janeen Arbuckle, 
and Rhiannon Reed who represent appropriate expertise (maternal health, neonatology, clinical 
trials, and biostatistics). They will provide oversight to assure that the trial accrues at a sufficient 
rate and that the safety and privacy of all study participants is assured. Members of the DSMB 
are not involved in any aspect of the trial operation. The DSMB will be provided progress reports 
and adverse event reports on a monthly basis to review study progress and monitor adverse 
events. 
2. Adverse events reporting: Detailed information concerning adverse events will be collected and 
evaluated throughout the trial. The DSMB will review all Adverse Event Report forms and other 
safety data.  
 
7 Future Studies 
 
 
 


23 
 
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