Acute Pain Management:

Migraine Headaches

October 26, 2019

Arezou Teimouri & Dr. Maureen Allen

Choosing Wisely Academic Detailing Conference

Disclosures

▰ Arezou Teimouri, RPh

▻ BPharm, MPharmSci

▻ Drug Evaluation Unit

▻ No conflicts of interest

▰ Dr. Maureen Allen

▻ MD, CCFP-EM(PC), FCFP

▻ Family and Emergency

Medicine

▻ No conflicts of interest

2

Objectives

Review the evidence for:

▰ Acetaminophen

▰ Acetaminophen with codeine combination

▰ Non-steroidal anti-inflammatory drugs (NSAIDs)

for classic migraine headache treatment in outpatient settings.

3

Patient Case: JP

4

JP

▰ 44 year old male

▰ PMH: Classic Migraine Headaches (without aura) x 2

years

▰ Has occasional migraines (~7/year, started after getting

a new job)

▰ Current medication: acetaminophen 500 mg prn with

minimal relief

▰ He recently heard of a new powdered drug that is mixed

with water, that’s supposedly better for migraines

▰ Wants to know if that would be the best option

5PMH: past medical history; PRN: as needed/as required

Background

Classic Migraine Headaches

6

Classic Migraine Headache: Without Aura

International Headache Society Criteria

7

“

”

Worthington I et al. Can J Neurol Sci. 2013; 40(5), Suppl.3 – S5

Classic Migraine Headache: With Aura

8

International Headache Society Criteria

Worthington I et al. Can J Neurol Sci. 2013; 40(5), Suppl.3 – S5

“

”

Goals of Pharmacotherapy

Relieve:

▰ Pain rapidly and consistently

▻ Pain-free within two hours

▰ Associated symptoms (e.g., nausea,

vomiting, photophobia, phonophobia)

▰ Migraine-related disability (return to normal

function)

Minimal or no adverse events.

9

Worthington I et al. Can J Neurol Sci. 2013; 40(5), Suppl.3 – S6

Acute Migraine Headache Treatment Algorithm

10

Mild-Moderate

• Acetaminophen

• NSAIDs

Moderate-Severe

• NSAIDs + triptan rescue

• Triptans

Refractory• Triptan + NSAID combination

± rescue therapy

• Dihydroergotamine

± metoclopramide

prn for

nausea/vomiting*Opioid (i.e., codeine)-

containing medications

and tramadol-containing

medications are not

recommended for routine

use

Worthington I et al. Can J Neurol Sci. 2013; 40(5), Suppl.3 – S33-62

EVIDENCE REVIEW 11

Important Terminology

▰ Pain-free Outcome

▻ Moderate or severe

pain to none

▻ Pre-specified time

interval (e.g. 2 hours)

▻ Desired by

International Headache

Society (IHS)

▰ Headache Response

▻ “Pain relief”

▻ “Headache relief”

▻ Decrease in headache

intensity from moderate or

severe to mild or none

▻ Pre-specified time

intervals (1, 2, or 4 hours)

12

Worthington I et al. Can J Neurol Sci. 2013; 40(5), Suppl.3 – S11

Important Terminology Continued…

▰ Sustained pain-free

▻ The number (%) of

patients pain-free at

2 hours (h) + over

the next 22 h

(without rescue)

▰ Headache recurrence

▻ re-emergence of

moderate-severe

headache (within 24 h)

after initial response

13

Worthington I et al. Can J Neurol Sci. 2013; 40(5), Suppl.3 – S11

Acetaminophen

Evidence Review for Migraines

14

“ Derry S, Moore R. Paracetamol

(acetaminophen) with or without an

antiemetic for acute migraine headaches in

adults. Cochrane Database Syst Rev.

2013, Issue 4. Art. No.: CD008040. DOI:

10.1002/14651858.CD008040.pub3

1515

Cochrane Review: Acetaminophen

16

PatientsAdults ≥18 years of age Migraine diagnosis based on International Headache Society Criteria

InterventionParacetamol (acetaminophen) 1000 mg ± an antiemetic (self-administered)

Comparator(s)Placebo, active-treatments

Outcome(s)

Primary outcomes:

Pain-free at 2 h, without the use of rescue medication

Reduction in headache pain (‘headache relief’) at 2 h

Derry S, Moore R. Cochrane Database Syst Rev. 2013 (4).

Paracetamol 1000 mg vs. Placebo

17

OutcomeEvent rate

RR

95% CI

NNT/NNH

95% CIParacetamol

1000 mg

Placebo

Pain-free response at 2 h19% 10%

1.8

(1.2-2.6)

12

(7.5-32)

Headache relief at 2 h56% 36%

1.6

(1.3-1.8)

5.0

(3.7-7.7)

At least one AE18% 23%

0.78

(0.64-0.95)

21

(11-300)

Serious AE Insufficient Data

Derry S, Moore R. Cochrane Database Syst Rev. 2013 (4).

AE: adverse event; NNH: number needed to harm; NNT: number needed to treat; RR: risk ratio

Paracetamol 1000 mg vs. Placebo

18

NNH 21At least one AE

NNT 12 Pain-free response at 2 h

NNT 5.0Headache relief at 2 h

Derry S, Moore R. Cochrane Database Syst Rev. 2013 (4).

Quality of

Evidence

(GRADE) =

Low

3 studies (n=717)

4 studies (n=1293)

3 studies (n=717)

What about acetaminophen with codeine?

19

“ Boureau F, Joubert JM, Lasserre V,

Prum B, Delecoeuillerie G. Double-

blind comparison of an acetaminophen

400 mg-codeine 25 mg combination

versus aspirin 1000 mg and placebo in

acute migraine attack. Cephalalgia

1994 04/01;14(2):156-161.

20

RCT: Acetaminophen + Codeine

21

Boureau F, Joubert JM, Lasserre V, et al. Cephalalgia. 1994 04/01;14(2):156-161.

P18-65 years of age, migraine without aura based on International Headache Society

criteria with onset before age 50

(n=247)

IAcetaminophen 400 mg combined with codeine 25 mg (ACC)

CAspirin 1000 mg, Placebo

(Randomized, double-blind, double-dummy trial with cross-over during three periods).

OPrimary efficacy measure: complete or near-complete relief of pain after 2 h (score of 0 or 1

on a four-point verbal scale)

Acetaminophen + Codeine vs. Aspirin vs.

Placebo

22

Boureau F, Joubert JM, Lasserre V, et al. Cephalalgia. 1994 04/01;14(2):156-161.

OutcomeEvent rate Statistical Significance

Placebo Aspirin

1000 mg

ACC

400/25 mg

Complete or almost

complete relief of

headache after 2 h29.8% 52.3% 49.7%

NSS between aspirin vs. ACC

Both aspirin and ACC significantly

different from placebo (p=0.0003

and p=0.0002)

Complete relief after 2 h11.1% 22.0% 18.4%

NSS between the three groups

(p=0.08)

At least one AE 13.7% 14.7% 18.4%NSS difference between the

three groups (p=0.99)

Serious AE None

ACC: acetaminophen 400 mg + codeine 25 mg; AE: adverse event; NNS: not statistically significant

Canadian Guidelines

Canadian guideline on acute drug therapy for

migraine headaches (2013)1:

▰ codeine-containing combinations: a last

line/alternative option if no response or

contraindications to first-line options

Canadian review/guideline for primary care

management of headache in adults (2015)2:

▰ fixed-dose combination analgesics that include

codeine = a last line option

23

1Worthington I et al. Can J Neurol Sci. 2013; 40(5), Suppl.3 – S33-62; 2Becker WJ et al. Can Fam Physician. 2015; 61(8):670-9.

Weak Recommendation –

Low-quality evidence

(Not for routine use)1

RxTx Algorithm for Management of Acute Migraine 24

Purdy, R.A. Headache in Adults. RxTx, Compendium of Therapeutic Choices, Canadian Pharmacists Association. 2019.

Choosing Wisely

25

American Headache Society and American Academy of Neurology: Five Things Physicians and Patients Should Question Handouts. Choosing Wisely.

NSAIDs

Evidence Review for Migraines

26

NSAIDs: Mechanism of Action

27

Non-selective

NSAIDs

Aspirin

COX-2 Inhibitors

Non-selective

NSAIDs

Aspirin (irreversible

inhibition – slightly

more selective)

Attribution-NonCommercial 3.0 Unported (CC BY-NC 3.0) - https://www.dovepress.com/risk-of-stroke-associated-with-nonsteroidal-anti-inflammatory-drugs-peer-reviewed-fulltext-article-VHRM

CPhA Monograph. Nonsteroidal Anti-inflammatory Drugs (NSAIDs). 2014.

NSAIDs with Evidence: Cochrane Reviews

28

(Derry et al., 2013) (Rabbie et al., 2013) (Kirthi et al., 2013) (Law et al., 2013)

PAdults ≥18 years of age

Migraine diagnosis based on International Headache Society Criteria

IDiclofenac potassium ±

an antiemetic

Ibuprofen ± an

antiemetic

Aspirin ± an

antiemetic

Naproxen ± an

antiemetic

CPlacebo, active-treatments

O

Primary outcomes:

Pain-free at 2 h, without the use of rescue medication

Reduction in headache pain (‘headache relief’) at 2 h

Diclofenac Potassium vs. Diclofenac Sodium

29

Altman R, Bosch B, Brune K et al. Drugs. 2015;75(8):859–877.

More water

soluble

Rapid dissolution

Faster absorption

Rapid onset of

pain relief

Diclofenac Potassium

Diclofenac Potassium 50 mg vs. Placebo

30

OutcomeEvent rate

RR

95% CI

NNT/NNH

95% CIDiclofenac 50 mg

(tablet + powder)

Placebo

Pain free response at 2 h(2 RCTs, n=1447) 22% 11%

2.0

(1.6-2.6)

8.9

(6.7-13)

Headache relief at 2 h(2 RCTs, n=1447) 55% 39%

1.5

(1.3-1.7)

6.2

(4.7-9.1)

At least one AE(3 RCTs, n=1075) 18% 16%

1.1

(0.86-1.5)NSS

Serious AE No serious AEs reported

Derry S, Rabbie R, Moore RA. Cochrane Database Syst Rev. 2013 (4).

AE: adverse event; NNH: number needed to harm; NNT: number needed to treat; NSS: not statistically significant; RCT: randomized controlled trial; RR: risk ratio

Diclofenac Potassium: Soluble Formulations

For soluble (powder/sachet) formulation only vs. placebo

Pain-free at 2 h: (2 RCTs, n=1083)

▰ RR 2.3 (95% CI 1.7-3.1), NNT 7.4 (5.6-11)

Headache relief at 2 h: (2 RCTs, n=1083)

▰ RR 1.5 (1.3-1.7), NNT 5.1 (4.0-7.0)

31

Derry S, Rabbie R, Moore RA. Cochrane Database Syst Rev. 2013 (4).

Diclofenac 50 mg (both tablet and

soluble formulations)

Pain-free response at 2 h NNT 8.9 (6.7-13)

Headache relief at 2 h NNT 6.2 (4.7-9.1)

Ibuprofen 400 mg vs. Placebo

32

OutcomeEvent rate RR

95% CI

NNT/NNH

95% CIIbuprofen 400 mg Placebo

Pain-free response at 2 h(6 RCTs, n=2575) 26% 12%

1.9

(1.6-2.3)

7.2

(5.9-9.2)

Headache relief at 2 h(7 RCTs, n=1815) 57% 25%

2.2

(1.9-2.5)

3.2

(2.8-3.7)

At least one AE(7 RCTs, n=1767) 15% 19%

0.97

(0.82-1.2)NSS

Serious AE Insufficient data

Rabbie R, Derry S, Moore RA. Cochrane Database Syst Rev. 2013 (4).

AE: adverse event; NNH: number needed to harm; NNT: number needed to treat; NSS: not statistically significant; RCT: randomized controlled trial; RR: risk ratio

Ibuprofen: Does dosing matter?

Ibuprofen 200 mg vs. placebo

Pain-free at 2 h: (2 RCTs, n=777)

▰ RR 2.0 (95% CI 1.4-2.8), NNT 9.7 (6.5-18)

Headache relief at 2 h: (2 RCTs, n=777)

▰ RR 1.4 (1.2-1.6), NNT 6.3 (4.4-11)

At least one AE: (2 RCTs, n=780)

▰ RR 0.85 (0.67-1.1), NSS

33

Rabbie R, Derry S, Moore RA. Cochrane Database Syst Rev. 2013 (4).

Ibuprofen 400 mg

NNT 7.2 (5.9-9.2)

Ibuprofen 400 mg

NNT 3.2 (2.8-3.7)

Ibuprofen 400 mg

RR 0.97 (0.82-1.2), NSS

Aspirin 900 mg or 1000 mg vs. Placebo

34

OutcomeEvent rate

RR

95% CI

NNT/NNH

95% CIAspirin 900 mg

or 1000 mg

Placebo

Pain-free response at 2 h(6 RCTs, n=2027) 24% 11%

2.1

(1.7-2.6)

8.1

(6.4-11)

Headache relief at 2 h(6 RCTs, n=2027) 52% 32%

1.6

(1.5-1.8)

4.9

(4.1-6.2)

At least one AE(7 RCTs, n=2458) 14% 11%

1.3

(1.02-1.6)

34

(18-340)

Serious AE Insufficient data

Kirthi V, Derry S, Moore RA. Cochrane Database Syst Rev. 2013 (4).

AE: adverse event; NNH: number needed to harm; NNT: number needed to treat; RCT: randomized controlled trial; RR: risk ratio

Naproxen 500 mg or 825 mg vs. Placebo

35

OutcomeEvent rate

RR

95% CI

NNT/NNH

95% CINaproxen 500 mg

or 825 mg

Placebo

Pain-free response at 2 h(4 RCTs, n=2149) 17% 8.5%

2.0

(1.6-2.6)

11

(8.7-17)

Headache relief at 2 h(4 RCTs, n=2149) 45% 29%

1.6

(1.4-1.8)

6.0

(4.8-7.9)

At least one AE(4 RCTs, n=2174) 15% 12%

1.3

(1.1-1.6)

28

(15-132)

Serious AE Insufficient data

Law S, Derry S, Moore RA. Cochrane Database Syst Rev. 2013 (10).

AE: adverse event; NNH: number needed to harm; NNT: number needed to treat; RCT: randomized controlled trial; RR: risk ratio

Naproxen: Does dosing matter?

36

Naproxen 500 mg alone vs. placebo

Pain-free at 2 h: (3 RCTs, n=1951)

▰ NNT 13 (9.7-22), NSS from NNT for combined dosage

Headache relief at 2 h: (3 RCTs, n=1951)

▰ NNT 6.2 (4.9-8.3), NSS from NNT for combined dosage

At least one AE: (3 RCTs, n=1951)

▰ RR 1.2 (0.96-1.5), NSS

Combined dosage

NNT 11 (8.7-17)

Combined dosage

NNT 6.0 (4.8-7.9)

Combined dosage

NNH 28 (15-132)

Law S, Derry S, Moore RA. Cochrane Database Syst Rev. 2013 (10).

NSAIDs with Evidence: Results

37

NSAID

(Derry et al., 2013) (Rabbie et al., 2013) (Kirthi et al., 2013) (Law et al., 2013)

Outcome

(NSAID vs. Placebo)

Diclofenac

potassium (50 mg)

Ibuprofen

(400 mg)

Aspirin

(900 mg or 1000 mg)

Naproxen

(500 mg or 825 mg)

Pain-free response at 2 h NNT 8.9 (6.7-13) NNT 7.2 (5.9-9.2) NNT 8.1 (6.4-11) NNT 11 (8.7-17)

Headache relief at 2 h NNT 6.2 (4.7-9.1) NNT 3.2 (2.8-3.7) NNT 4.9 (4.1-6.2) NNT 6 (4.8-7.9)

Sustained pain-free

during the 24 h post

dose

NNT 9.5 (7.2-14) No data No data NNT 19 (13-34)

Sustained headache

relief during the 24 h

post dose

No data NNT 4.0 (3.2-5.2) NNT 6.6 (4.9-10) NNT 8.3 (6.4-12)

At least one AE RR 1.1 (0.86 to 1.6) RR 0.97 (0.82-1.2) NNH 34 (18-340) NNH 28 (15-132)

Serious AE No events Insufficient data Insufficient data Insufficient dataAE: adverse event; NNH: number needed to harm; NNT: number needed to treat; NSAID: non-steroidal anti-inflammatory drug; RR: risk ratio

Note: this table is a compilation of outcomes from separate Cochrane reviews. Any comparisons made from this table are indirect. All 95% confidence intervals.

Other considerations for JP:

▰ Cost:

▻ Diclofenac potassium 50 mg powder $102.15/box of 9 sachets

▻ Ibuprofen 200 mg $5.43/100 tabs; Ibuprofen 400 mg $10.10/100 tabs

▰ Administration:

▻ Diclofenac potassium 50 mg powder: mix one sachet with 1-2 ounces of

water (no other liquid)1

▻ Ibuprofen: take tablet/caplet/liquid-gel with 250 mL glass of water

▰ Comorbidities/Contraindications

38

1Product Monograph. Cambia® (diclofenac potassium). 2018.

Back to JP: What would you tell him?

▰ JP’s acetaminophen dose (500 mg) is

considered low – could try 1000 mg.

▰ Ibuprofen 400 mg is also a suitable first

line option.

▰ If he prefers diclofenac potassium

powder, cost is an important factor to

consider.

39

Bottom Line

▰ Acetaminophen or NSAIDs (ASA, Naproxen,

Ibuprofen, Diclofenac potassium) = 1st line

(consider patient-specific factors)

▰ Avoid acetaminophen with codeine

combination routine use (last line therapy)

▰ Consider dosing/formulation differences prior

to changing therapy

40

Tools for Prescribers

Canadian Guidelines

https://headachesociety.ca/guidelines/

American Guidelines

https://americanheadachesociety.org/resources/guidelines/guidelines-position-statements-evidence-assessments-and-consensus-opinions/

UK Guidelines

https://www.guidelines.co.uk/pain/sign-migraine-guideline/454046.article

Choosing Wisely. American Academy of Neurology: Five Things Physicians and Patients Should Question

http://www.choosingwisely.org/wp-content/uploads/2015/02/AAN-Choosing-Wisely-List_09-2019.pdf

Choosing Wisely. American Headache Society. Five Things Physicians and Patients Should Question

https://americanheadachesociety.org/wp-content/uploads/2018/06/Choosing-Wisely-Flyer.pdf

Choosing Wisely. American Academy of Neurology: Treating Migraine Headaches

http://www.choosingwisely.org/patient-resources/treating-migraine-headaches/

CORE Neck Tool and Headache Navigator

https://cep.health/clinical-products/core-neck-tool-and-headache-navigator/

Toward Optimized Practice

http://www.topalbertadoctors.org/cpgs/1006541

Tools for Patients

42

Choosing Wisely. American Academy of Neurology: Five Things Physicians and Patients Should Question

http://www.choosingwisely.org/wp-content/uploads/2015/02/AAN-Choosing-Wisely-List_09-2019.pdf

Choosing Wisely. American Headache Society. Five Things Physicians and Patients Should Question

https://americanheadachesociety.org/wp-content/uploads/2018/06/Choosing-Wisely-Flyer.pdf

Choosing Wisely. American Academy of Neurology: Treating Migraine Headaches

http://www.choosingwisely.org/patient-resources/treating-migraine-headaches/

American Migraine Foundation

https://americanmigrainefoundation.org/

MedlinePlus: Migraine

https://medlineplus.gov/migraine.html

IMAGES

https://pixabay.com/illustrations/brain-inflammation-stroke-medical-3168269/

https://pixabay.com/illustrations/headache-aspirin-head-migraine-4367062/

https://pixabay.com/illustrations/drug-pill-medicine-health-1674890/

https://pixabay.com/illustrations/magnifying-glass-search-to-find-1020142/

https://pixabay.com/illustrations/question-mark-question-response-1019993/

Attribution-NonCommercial 3.0 Unported (CC BY-NC 3.0) - https://www.dovepress.com/risk-of-stroke-associated-with-nonsteroidal-anti-inflammatory-drugs-peer-reviewed-fulltext-article-VHRM

https://pixabay.com/vectors/stomach-icon-stomach-icon-gut-2316627/

https://pixabay.com/illustrations/problem-success-result-business-3804254/

https://pixabay.com/illustrations/question-mark-question-response-1020165/

43

Credits: Presentation template by SlidesCarnival

REFRENCES

▰ Worthington I, Pringsheim T FAU - Gawel, Marek, J., FAU GM, Gladstone JF, Cooper PF, Dilli EF, et al. Canadian Headache Society Guideline: acute drug

therapy for migraine headache. Can J Neurol Sci. 2013; 40(5), Suppl.3, S1-S32.

▰ Derry S, Moore R. Paracetamol (acetaminophen) with or without an antiemetic for acute migraine headaches in adults. Cochrane Database Syst Rev. 2013, Issue

4. Art. No.: CD008040. DOI: 10.1002/14651858.CD008040.pub3

▰ Boureau F, Joubert JM, Lasserre V, Prum B, Delecoeuillerie G. Double-blind comparison of an acetaminophen 400 mg-codeine 25 mg combination versus aspirin

1000 mg and placebo in acute migraine attack. Cephalalgia 1994 04/01;14(2):156-161.

▰ Becker WJ, Findlay T, Moga C, Scott NA, Harstall C, Taenzer P. Guideline for primary care management of headache in adults. Can Fam Physician. 2015;

61(8):670-9.

▰ Purdy, R.A. Headache in Adults. RxTx, Compendium of Therapeutic Choices, Canadian Pharmacists Association. 2019. Available with subscription. Accessed

10/11/2019.

▰ American Headache Society. Five Things Physicians and Patients Should Question. Choosing Wisely. 2018. Available from

https://americanheadachesociety.org/wp-content/uploads/2018/06/Choosing-Wisely-Flyer.pdf. Accessed 10/18/2019

▰ American Academy of Neurology. Five Things Physicians and Patients Should Question. Choosing Wisely. 2015. Available from http://www.choosingwisely.org/wp-

content/uploads/2015/02/AAN-Choosing-Wisely-List_09-2019.pdf Accessed 10/18/2019

▰ CPhA Monograph. Nonsteroidal Anti-inflammatory Drugs (NSAIDs). Canadian Pharmacists Association. 2014. Available with subscription to CPS. Accessed

10/18/2019.

▰ Rabbie R, Derry S, Moore RA. Ibuprofen with or without an antiemetic for acute migraine headaches in adults. Cochrane Database of Syst Rev. 2013(4)

▰ Derry S, Rabbie R, Moore RA. Diclofenac with or without an antiemetic for acute migraine headaches in adults. Cochrane Database of Syst Rev. 2013(4).

▰ Kirthi V, Derry S, Moore RA. Aspirin with or without an antiemetic for acute migraine headaches in adults. Cochrane Database of Syst Rev. 2013(4).

▰ Law S, Derry S, Moore RA. Naproxen with or without an antiemetic for acute migraine headaches in adults. Cochrane Database of Syst Rev. 2013(10).

▰ Altman R, Bosch B, Brune K, Patrignani P, Young C. Advances in NSAID development: evolution of diclofenac products using pharmaceutical technology. Drugs.

2015;75(8):859–877. doi:10.1007/s40265-015-0392-z

▰ Product Monograph. Cambia® (diclofenac potassium). 2018. Available from https://pdf.hres.ca/dpd_pm/00045482.PDF. Accessed10/11/2019 44

45

Questions?