Pain, 44 (1991) 151-15s 0 1991 Elsevier Science Publishers ADONIS 0304395991000695
151 B.V. 0304-3959/91/$03.50
PAIN 01728
The analgesic effects of caffeine in headache Nicholas
Ward
a, Coralyn
Whitney
b, David
Avery
a and David
Dunner
a
a Department of Psychiatry and Behavioral Sciences and h Department of Dental Public Health Sciences, University of Washington, Seattle, (Received
5 February
WA (U.S.A.)
1990, revision received
30 July 1990, accepted
10 August
1990)
Caffeine is frequently added to mild analgesic preparations but its effect when used alone on pain has Summary never been studied in humans. Using a double-blind placebo-controlled multiple crossover design, 53 patients with non-migrainous headaches were given placebo, acetaminophen, 2 doses of caffeine and 2 combinations of caffeine with acetaminophen. Caffeine appeared to have independent analgesic effects that were equivalent to acetaminophen and were still significant when statistical adjustments were made for prior caffeine consumption and caffeine’s effects on mood. Key words: Caffeine;
Analgesic
effects;
Headache
Introduction Several studies in humans have reported that caffeine when added to aspirin or acetaminophen gives significantly more pain relief than aspirin or acetaminophen alone [8]. Despite this finding, no human studies have assessed whether caffeine alone has independent analgesic effects. Even the efficacy of intravenous caffeine for postdural puncture headache [6] may be a consequence of vasoconstriction [10,14] and hence does not provide proof that caffeine has independent analgesic properties. Attempts to assess analgesic activity of caffeine in animals have yielded conflicting results. Analgesic properties have depended on type of pain stimulus [16,17,19,23] (mechanical, thermal or electrical), and assessment has been confounded by caffeine’s ability to increase the response speed used to measure analgesia. Thus, human studies that rely on verbal reports of pain and use clinically relevant doses are preferable to adequately test potential analgesic properties of caffeine. Three major hypotheses concerning potential effects of caffeine on headache were tested in this study: (1) Caffeine alone is an analgesic that directly and independently reduces pain. (2) Caffeine improves mood [9] and
Correspondence to: Nicholas G. Ward, M.D., Department of Psychiatry and Behavioral Sciences, RP-10, University of Washington, Seattle, WA 98195, U.S.A.
thus indirectly reduces reported pain. Because there is evidence that mood can affect reported pain [7,22,24,25], measurements of mood during caffeine trials are necessary in order to statistically adjust for mood effects and determine if there is a main effect on pain. (3) Caffeine reduces headache pain by successfully treating a subgroup with caffeine withdrawal headache [4] or migraine. Therefore, patients with migraine headaches should be eliminated from the study and the extent of caffeine consumption prior to the headache’s onset needs to be recorded and controlled for in the statistical analysis.
Method Subject selection Subjects, aged 18-60, were recruited by means of a newspaper advertisement asking for people who frequently had headaches. All signed informed consent forms in accord with the University of Washington Human Subjects Review Committee. Subjects were included if they reported at least 6 headaches/month during the past 3 months with pain severity averaging 2 or greater on a 1 (mild) to 5 (excruciating) pain scale. Because caffeine could relieve migraine headache through its vasoconstrictive properties [10,14], only individuals with no history of migraines and with headaches that had no migrainous features were included. Headaches with migrainous features were defined as unilateral or bilateral headaches that were throbbing in
the beginning and accompanied by at least one symptom suggestive of prodromata (scotoma. contralateral neurological manifestations a few minutes prior to the attack, vague prodroma hours to days prior to the attack usually stereotyped for the patient) and/or the headache was accompanied by photophobia, vomiting, constipation, diarrhea or other physiologic symptoms vertigo, chills, abdominal distension. etc.). All (e.g., subjects were screened by a faculty-level psychiatrist using a semistructured interview format for psychiatric and medical problems. Those with significant medical problems (active G.I., hepatic. renal, endocrine or convulsive disorder, or malignancy), alcoholism within the last 24 months, major psychiatric disorders or history of chronic analgesic or tranquilizer use were excluded from the study. Treatment All subjects were crossed over in a double-blind fashion to receive 6 different 2-tablet doses of the following: (1) placebo, (2) 65 mg caffeine (C65), (3) 130 mg caffeine (C130), (4) 648 mg acetaminophen (A), (5) 648 mg acetaminophen + 65 mg caffeine (A + C65). (6) 648 mg acetaminophen + 130 mg caffeine (A + Cl30). The dose of 648 mg acetaminophen was chosen because this was equal to 2 standard dose pills in the U.S., and the dose of 65 mg caffeine was equal to the standard amount added to 1 combination pill. As a reference, a cup of strong coffee typically contains between 80 and 120 mg of caffeine. Subjects were randomly assigned to 1 of 6 possible treatment sequences (listed in Table Ill) so that at the end of the study, each treatment would be preceded equally by each of the other treatments. Subjects were instructed to take medications if they had a headache rated 2 or greater on the McGill Pain Questionnaire (MPQ) [12], had not taken any analgesic in the prior 6 h and the headache occurred at least 6 h before bedtime. Only 1 test dose could be taken on any given day, and no caffeine or analgesics could be consumed during the 2 h medication trial. Just before taking the medication, subjects completed a form documenting the amount of caffeine containing beverages consumed during the prior 24 h, the MPQ. the Profile of Mood States [ll] (POMS) and a word-anchored visual analog (VA) pain scale using a 10 cm line with “no pain” at the left end, “pain as bad as it could be” at the right end and “mild, moderate, severe” written in sequence beneath the line. At intervals of 60 and 120 min, subjects completed the POMS and VA pain scale. and at 30 min the VA pain scale alone. Data analysis The dependent variables and covariates analyzed were the visual analog pain and the POMS mood scores, and prior caffeine consumption. Pain and mood scores were calculated as change from baseline to statistically
account for possible differences in baseline values. The independent factors used in the analysis were type 01 medication. sequence of medication. and time after taking (0.5. 1. 2 h) medication. The significance of factors and covariates was determined by the analysis of covariance (ANCOVA) programs for repeated measures (BMDP). Because it was hypothesized in advance that active medications were better than placebo. comparisons of active medications to placebo were one-sided. All other mean comparisons were two-sided and performed at the 0.05 alpha level. In order to determine if there were separate medication effects, the following special multiple comparison procedures [21] were used to maintain the nominal 0.05 level: Dunnett’s t test for comparing active medications to placebo and Tukey’s I test for comparing the active medications that differ from placebo to the other medications. The overall order of medication effects across sequences was evaluated using ANOVA.
Results Effects on pain Of the original 60 subjects who finished the study, 7 were dropped from the analysis because of missing VA pain scores, leaving 17 males and 36 females between the ages of 20 and 60 (mean age 37.4 + 10 SD.) who completed the study. In all of the following analyses, the effect of gender was evaluated but no gender differences were found. As can be seen in Fig. 1 and Table I at 2 h, all active treatments were associated with significantly greater reduction on the visual analog (VA) pain scale than was placebo. At 30 min and 1 h, the 2 treatments with 130 mg caffeine (C130) and A + C130, and the acetaminophen with 65 mg caffeine treatment demonstrated significantly (P < 0.05) greater reduction of VA pain than placebo. At 2 h there was a non-signifi-
30.
Y
a
o
A---.0
30
120
60 Time in Minutes
Fig. 1. Pain reduction:
comparisons
of different
treatments.
153 TABLE
I
MEAN SCORES IN mm ( + / - SE.) OF VISUAL ANALOG PAIN (N = 53) Medication
Baseline
Time in min 30
60
120
1. Placebo
48.51 (1.96)
40.83 (2.41)
36.62 (2.79)
36.22 (3.12)
2. Acct. only
54.11 (2.52)
44.36 (3.03)
37.69 (3.03)
31.90 b (3.30)
3. A+C65
53.03 (2.47)
41.66 (2.88)
34.98 = (2.97)
26.21 d (3.28)
4. A+C130
49.75 (2.44)
36.07 a (2.45)
27.81 = (2.77)
21.26 d (2.76)
5. C65
51.62 (2.14)
41.60 (2.75)
34.41 (3.05)
29.45 ’ (3.02)
6. Cl30 -
54.96
41.15 a
33.98 b
31.55 =
Significantly greater change from baseline than placebo. = P < 0.05. h P
151 B.V. 0304-3959/91/$03.50
PAIN 01728
The analgesic effects of caffeine in headache Nicholas
Ward
a, Coralyn
Whitney
b, David
Avery
a and David
Dunner
a
a Department of Psychiatry and Behavioral Sciences and h Department of Dental Public Health Sciences, University of Washington, Seattle, (Received
5 February
WA (U.S.A.)
1990, revision received
30 July 1990, accepted
10 August
1990)
Caffeine is frequently added to mild analgesic preparations but its effect when used alone on pain has Summary never been studied in humans. Using a double-blind placebo-controlled multiple crossover design, 53 patients with non-migrainous headaches were given placebo, acetaminophen, 2 doses of caffeine and 2 combinations of caffeine with acetaminophen. Caffeine appeared to have independent analgesic effects that were equivalent to acetaminophen and were still significant when statistical adjustments were made for prior caffeine consumption and caffeine’s effects on mood. Key words: Caffeine;
Analgesic
effects;
Headache
Introduction Several studies in humans have reported that caffeine when added to aspirin or acetaminophen gives significantly more pain relief than aspirin or acetaminophen alone [8]. Despite this finding, no human studies have assessed whether caffeine alone has independent analgesic effects. Even the efficacy of intravenous caffeine for postdural puncture headache [6] may be a consequence of vasoconstriction [10,14] and hence does not provide proof that caffeine has independent analgesic properties. Attempts to assess analgesic activity of caffeine in animals have yielded conflicting results. Analgesic properties have depended on type of pain stimulus [16,17,19,23] (mechanical, thermal or electrical), and assessment has been confounded by caffeine’s ability to increase the response speed used to measure analgesia. Thus, human studies that rely on verbal reports of pain and use clinically relevant doses are preferable to adequately test potential analgesic properties of caffeine. Three major hypotheses concerning potential effects of caffeine on headache were tested in this study: (1) Caffeine alone is an analgesic that directly and independently reduces pain. (2) Caffeine improves mood [9] and
Correspondence to: Nicholas G. Ward, M.D., Department of Psychiatry and Behavioral Sciences, RP-10, University of Washington, Seattle, WA 98195, U.S.A.
thus indirectly reduces reported pain. Because there is evidence that mood can affect reported pain [7,22,24,25], measurements of mood during caffeine trials are necessary in order to statistically adjust for mood effects and determine if there is a main effect on pain. (3) Caffeine reduces headache pain by successfully treating a subgroup with caffeine withdrawal headache [4] or migraine. Therefore, patients with migraine headaches should be eliminated from the study and the extent of caffeine consumption prior to the headache’s onset needs to be recorded and controlled for in the statistical analysis.
Method Subject selection Subjects, aged 18-60, were recruited by means of a newspaper advertisement asking for people who frequently had headaches. All signed informed consent forms in accord with the University of Washington Human Subjects Review Committee. Subjects were included if they reported at least 6 headaches/month during the past 3 months with pain severity averaging 2 or greater on a 1 (mild) to 5 (excruciating) pain scale. Because caffeine could relieve migraine headache through its vasoconstrictive properties [10,14], only individuals with no history of migraines and with headaches that had no migrainous features were included. Headaches with migrainous features were defined as unilateral or bilateral headaches that were throbbing in
the beginning and accompanied by at least one symptom suggestive of prodromata (scotoma. contralateral neurological manifestations a few minutes prior to the attack, vague prodroma hours to days prior to the attack usually stereotyped for the patient) and/or the headache was accompanied by photophobia, vomiting, constipation, diarrhea or other physiologic symptoms vertigo, chills, abdominal distension. etc.). All (e.g., subjects were screened by a faculty-level psychiatrist using a semistructured interview format for psychiatric and medical problems. Those with significant medical problems (active G.I., hepatic. renal, endocrine or convulsive disorder, or malignancy), alcoholism within the last 24 months, major psychiatric disorders or history of chronic analgesic or tranquilizer use were excluded from the study. Treatment All subjects were crossed over in a double-blind fashion to receive 6 different 2-tablet doses of the following: (1) placebo, (2) 65 mg caffeine (C65), (3) 130 mg caffeine (C130), (4) 648 mg acetaminophen (A), (5) 648 mg acetaminophen + 65 mg caffeine (A + C65). (6) 648 mg acetaminophen + 130 mg caffeine (A + Cl30). The dose of 648 mg acetaminophen was chosen because this was equal to 2 standard dose pills in the U.S., and the dose of 65 mg caffeine was equal to the standard amount added to 1 combination pill. As a reference, a cup of strong coffee typically contains between 80 and 120 mg of caffeine. Subjects were randomly assigned to 1 of 6 possible treatment sequences (listed in Table Ill) so that at the end of the study, each treatment would be preceded equally by each of the other treatments. Subjects were instructed to take medications if they had a headache rated 2 or greater on the McGill Pain Questionnaire (MPQ) [12], had not taken any analgesic in the prior 6 h and the headache occurred at least 6 h before bedtime. Only 1 test dose could be taken on any given day, and no caffeine or analgesics could be consumed during the 2 h medication trial. Just before taking the medication, subjects completed a form documenting the amount of caffeine containing beverages consumed during the prior 24 h, the MPQ. the Profile of Mood States [ll] (POMS) and a word-anchored visual analog (VA) pain scale using a 10 cm line with “no pain” at the left end, “pain as bad as it could be” at the right end and “mild, moderate, severe” written in sequence beneath the line. At intervals of 60 and 120 min, subjects completed the POMS and VA pain scale. and at 30 min the VA pain scale alone. Data analysis The dependent variables and covariates analyzed were the visual analog pain and the POMS mood scores, and prior caffeine consumption. Pain and mood scores were calculated as change from baseline to statistically
account for possible differences in baseline values. The independent factors used in the analysis were type 01 medication. sequence of medication. and time after taking (0.5. 1. 2 h) medication. The significance of factors and covariates was determined by the analysis of covariance (ANCOVA) programs for repeated measures (BMDP). Because it was hypothesized in advance that active medications were better than placebo. comparisons of active medications to placebo were one-sided. All other mean comparisons were two-sided and performed at the 0.05 alpha level. In order to determine if there were separate medication effects, the following special multiple comparison procedures [21] were used to maintain the nominal 0.05 level: Dunnett’s t test for comparing active medications to placebo and Tukey’s I test for comparing the active medications that differ from placebo to the other medications. The overall order of medication effects across sequences was evaluated using ANOVA.
Results Effects on pain Of the original 60 subjects who finished the study, 7 were dropped from the analysis because of missing VA pain scores, leaving 17 males and 36 females between the ages of 20 and 60 (mean age 37.4 + 10 SD.) who completed the study. In all of the following analyses, the effect of gender was evaluated but no gender differences were found. As can be seen in Fig. 1 and Table I at 2 h, all active treatments were associated with significantly greater reduction on the visual analog (VA) pain scale than was placebo. At 30 min and 1 h, the 2 treatments with 130 mg caffeine (C130) and A + C130, and the acetaminophen with 65 mg caffeine treatment demonstrated significantly (P < 0.05) greater reduction of VA pain than placebo. At 2 h there was a non-signifi-
30.
Y
a
o
A---.0
30
120
60 Time in Minutes
Fig. 1. Pain reduction:
comparisons
of different
treatments.
153 TABLE
I
MEAN SCORES IN mm ( + / - SE.) OF VISUAL ANALOG PAIN (N = 53) Medication
Baseline
Time in min 30
60
120
1. Placebo
48.51 (1.96)
40.83 (2.41)
36.62 (2.79)
36.22 (3.12)
2. Acct. only
54.11 (2.52)
44.36 (3.03)
37.69 (3.03)
31.90 b (3.30)
3. A+C65
53.03 (2.47)
41.66 (2.88)
34.98 = (2.97)
26.21 d (3.28)
4. A+C130
49.75 (2.44)
36.07 a (2.45)
27.81 = (2.77)
21.26 d (2.76)
5. C65
51.62 (2.14)
41.60 (2.75)
34.41 (3.05)
29.45 ’ (3.02)
6. Cl30 -
54.96
41.15 a
33.98 b
31.55 =
Significantly greater change from baseline than placebo. = P < 0.05. h P
