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Cephalalgia

30(12) 15351536

! International Headache Society 2010

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DOI: 10.1177/0333102410372426

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Letter to the Editor

Response to Comments on results of

Scher et al. pertaining to nonprescription

caffeine-containing combination

analgesics

Dear Sir We thank Drs Delzell and Haag for their letter

(1) supporting the cautious interpretation of the data in

(2). We are puzzled by their letter, as their comments

seem to fully agree with our manuscript. Their primary

criticism appears to be directed to less conservative

statements made in another manuscript whose authors

overlap with the present one (3).

We refer the interested reader to the introduction

and discussion (2), in which we discuss at length the

limitations of our and other evidence regarding medi-

cation type and medication overuse as risk factors for

headache progression/chronic daily headache (CDH).

To clarify our position, we agree that the available evi-dence on the association between nonprescription caf-

feine-containing combination analgesics and headache

progression is not sufficient to support definitive

causal inferences. Nor would we advocate making

definitive causal inferences regarding opiate- or bar-

biturate-containing analgesics and headache progres-

sion, although for these categories of treatment the

epidemiologic data are more consistent. Although Drs

Delzell and Haags comment relates to our findings

regarding caffeine-containing combination analge-

sicsnot a specific focus of our study as they note

the limitations of observational studies in this particu-

lar area apply to other forms of medication and the

related issue of whether treatment frequency is related

to risk of CDH (e.g. causes medication overuse

headache).

The absence of definitive evidence raises two key

questions. First, is it possible to gather evidence to sup-

port definitive inferences in this area? And second, in

the absence of definitive information, how should clini-

cians advise and treat their patients? We consider these

issues one at a time.

For studies of medication X as a risk factor for

migraine progression, the optimal study design is prob-

ably a randomized trial. Eligible patients would be ran-

domized to long-term acute treatment with medication

X or to an acute treatment alternative. Various limits

on treatment frequency might be added in both arms.

The endpoints might be the incidence of new-onset

chronic migraine/CDH, the proportion of patients

whose headaches increase in frequency by a pre-speci-

fied amount or a simple measured change in headache

or migraine days per month.

Because CDH is an event with an expected rate of

about 3% per year in unselected episodic headache or

migraine patients (4,5) and because we would want to

detect small differences in our non-superiority design,

such studies would need to be enormous. Even if we

used a design focused on a group at high risk for pro-

gression, hundreds of patients per arm and at least one

year of follow-up would be required. The choice of acute

treatment for the control group is problematic, as med-

ication X and the alternative treatment must be of equiv-alent efficacy and tolerability. Compliance over such a

long follow-up would also be problematic. Although

other designs, particularly randomized withdrawal stud-

ies, are possible, they answer a related but different ques-

tion. Finally, as a practical matter, such studies would

need to be conducted without industry funding for obvi-

ous reasons. Whether such a trial would be ethical is a

topic for a different discussion.

In the absence of definitive evidence, practicing clini-

cians need to make choices and provide advice to their

patients about acute treatment. Treatment guidelines

generally recommend restricting the use of any acute

treatments, including caffeine-containing combination

products, to two or at most three days per week (or 10

days per month) to reduce the risk of medication overuse

headache. The quality of evidence for this recommenda-

tion is low. It is not clear how many patients are helped

(by prevention of CDH) versus how many are hurt (by

pain under-treatment) by this advice, as this has not

been studied. Other treatments, including preventive

and behavioral methods, can be used to reduce headache

frequency and the need for acute medications.

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In conclusion, it is essential to obtain more definitive

information on the role of specific acute treatments,

and limits on use, as risk factors for the progression

of headache in general and migraine in particular.

Evidence from observational studies can be used to

inform the design of clinical trials but is inherently lim-

ited for the reasons stated in our study and elsewhere.Despite the extreme difficulty of designing and conduct-

ing interventional studies, we believe such studies are

needed, as CDH is not a rare condition, headache pro-

phylactic strategies and medication withdrawal thera-

pies do not work for a significant number of patients,

and it may be that more patients are harmed than

helped by current treatment guidelines.

References

1. Delzell E and Haag G. Comments on results of Scher et al.pertaining to nonprescription caffeine-containing combina-

tion analgesics. Cephalalgia 2010. E-pub ahead of print,

DOI: 10.1177/0333102410361540.

2. Scher AI, Lipton RB, Stewart WF, Bigal M. Patterns of

medication use by chronic and episodic headache sufferers

in the general population: results from the frequent head-

ache epidemiology study. Cephalalgia 2009; 30(3): 321328.

3. Bigal ME, Lipton RB. Overuse of acute migraine medica-

tions and migraine chronification. Curr Pain Headache

Rep 2009; 13: 301307.

4. Scher AI, Stewart WF, Ricci JA, Lipton RB. Factors

associated with the onset and remission of chronic daily

headache in a population-based study. Pain 2003; 106:

8189.

5. Bigal ME, Serrano D, Buse D, Scher A, Stewart WF,Lipton RB. Acute migraine medications and evolution

from episodic to chronic migraine: a longitudinal popula-

tion-based study. Headache 2008; 48: 11571168.

Ann Scher1, Richard Lipton2,3 and Marcelo Bigal2,4

1Uniformed Services University, USA2Albert Einstein College of Medicine, USA

3The Montefiore Headache Center, USA4Merck Inc., USA

Corresponding author:

Ann Scher

Department of Preventive Medicine and Biometrics

Uniformed Services University

4201 Jones Bridge Road Bethesda

MD, 20814 USA

Email: ascher@usuhs.mil

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