Effect of caffeine on acetaminophen analgesia. Effect of caffeine on ibuprofen analgesia in postoperative oral surgery pain. Caffeine as an analgesic adjuvant in tension headache. Caffeine as an analgesic adjuvant. A double-blind study comparing aspirin with caffeine to aspirin and placebo in patients with sore throat. Double-blind comparison of an acetaminophen-codeine-caffeine combination in oral surgery pain. A double-blind randomized study of an aspirin/caffeine combination versus acetaminophen/aspirin combination versus acetaminophen versus placebo in patients with moderate to severe post-partum pain. Aspirin and aspirin-caffeine in postpartum pain relief. The analgesic effects of caffeine in headache. Evaluation of aspirin, caffeine, and their combination in postoperative oral surgery pain. The fixed combination of acetylsalicylic acid, paracetamol and caffeine is more effective than single substances and dual combination for the treatment of headache: a multicentre, randomized, double-blind, single-dose, placebo-controlled parallel group study. Ibuprofen compared with ibuprofen plus caffeine after third molar surgery. Efficacy of a paracetamol and caffeine combination in the treatment of the key symptoms of primary dysmenorrhoea. Efficacy of low dose combination analgesics: acetaminophen/codeine, aspirin/butalbital/caffeine/codeine, and placebo in oral surgery pain.
Our objective was to determine the value of caffeine in combination with acetaminophen in the relief of pain from uterine cramping, episiotomy, and third molar extraction. In the dental study, 173 patients received two or four tablets of 500 mg acetaminophen or the combination of 500 mg acetaminophen and 65 mg caffeine. In the three postpartum studies, 1345 patients received one, two, or three tablets of acetaminophen, the combination, or a placebo. The mean scores for the summary variable percent sum of the pain intensity differences (% SPID) were higher in all for the combination than for acetaminophen alone, and in two studies the null hypothesis of no differences was rejected. The relative potency estimates for % SPID were 1.9, 1.8, and 1.3 for the three studies in which bioassays could be performed and the pooled relative potency was 1.7 with a 95% confidence interval of 1.1 to 3.1. The results were essentially the same among pain models and among patient groups with similar habitual caffeine consumption. Onset of analgesia was also faster with the combination. We conclude that caffeine enhances the analgesic efficacy of acetaminophen. Recent studies have demonstrated that caffeine acts as an analgesic adjuvant when combined with acetaminophen, aspirin, or their mixture. Our objective was to determine whether similar enhancement of analgesia could be demonstrated when caffeine is combined with ibuprofen. On a double-blind basis, a single oral dose of ibuprofen (50, 100, or 200 mg), a combination of ibuprofen, 100 mg, with caffeine, 100 mg, a combination of ibuprofen, 200 mg, with caffeine, 100 mg, or placebo was randomly assigned to 298 outpatients with postoperative pain after the surgical removal of impacted third molars. With a self-rating record, subjects rated their pain and its relief hourly for 8 hours. All active treatments were significantly superior to placebo, and the caffeine effect was significant for every measure of analgesia. Relative potency estimates indicated that the combination was 2.4 to 2.8 times as potent as ibuprofen alone. The combination also had a more rapid onset and longer duration of analgesic action. The analgesic adjuvancy of caffeine clearly extends to combinations with nonsteroidal anti-inflammatory drugs other than acetaminophen or aspirin. Six randomized, double-blind, two-period crossover studies, conducted under similar protocols, compared the efficacy of two analgesic combinations containing caffeine with an acetaminophen 1000 mg control and with a placebo in outpatients with episodic tension-type headaches. In four studies, comprising 1900 patients, the caffeine-containing analgesic consisted of a combination of 500 mg acetaminophen, 500 mg aspirin, and 130 mg caffeine (APAP/ASA/CAF). In two studies, comprising 911 patients, the caffeine-containing analgesic consisted of a combination of 1000 mg acetaminophen and 130 mg caffeine (APAP/CAF). Patients self-medicated for moderate or severe headache pain, and with a self-rating record they rated their pain and its relief hourly for 4 hours. In all six studies, the caffeine-containing analgesics were significantly superior both to placebo and to 1000 mg acetaminophen, and acetaminophen was significantly superior to placebo. The significant analgesic adjuvant effect of caffeine was independent of patients' usual caffeine use or their caffeine consumption in the 4 hours before medication. For each treatment, the pooled analgesic responses for the four studies of APAP/ASA/CAF were virtually superimposable on the responses in the two APAP/CAF studies. The combinations produced more stomach discomfort, nervousness, and dizziness than acetaminophen or placebo. Despite its frequent clinical use in analgesic agents, caffeine has not been accepted unequivocally as an analgesic adjuvant. To evaluate this activity of caffeine, we used new study methods in a randomized controlled trial on patients with acute sore throat due to tonsillopharyngitis. Patients were randomly assigned to receive a single dose of one of three treatments: 800 mg of aspirin with 64 mg of caffeine (n = 70), 800 mg of aspirin (n = 68), or placebo (n = 69). Under double-blind conditions, during a 2-hour evaluation period, patients used different rating scales to assess pain intensity, change in pain, relief, and two qualities of throat pain, how swollen the throat felt, and difficulty swallowing. Aspirin with caffeine and aspirin alone were significantly more effective than placebo for all efficacy measurements from 30 minutes through 2 hours and overall. The aspirin-caffeine combination also showed evidence of activity at 15 minutes on the relief scale. Aspirin with caffeine was more effective than aspirin alone after 30 minutes and over the entire study period. For patients with fever, both active treatments were equally effective antipyretic agents. We conclude, therefore, that 800 mg of aspirin, given alone or with 64 mg of caffeine, is an effective analgesic and antipyretic agent. Because the aspirin-caffeine combination is significantly more effective than aspirin alone as an analgesic, we also conclude that 64 mg of caffeine is an analgesic adjuvant. The purpose of this paper was to evaluate the contribution of low dosages of codeine and caffeine when added to acetaminophen. Subjects were dental outpatients undergoing oral surgery involving bone removal. This was a single-dose, parallel group, double-blind assay evaluting 99 subjects. The treatment groups were acetaminophen 1000 mg, acetaminophen 1000 mg + codeine 16 mg + caffeine 30 mg and placebo. The results demonstrated that both active treatments were superior to placebo. Overall, the combination was slightly better than acetaminophen alone. The advantage of the combination appeared more evident in the "severe" baseline pain group. In a double-blind, randomized controlled trial among 500 post-partum patients experiencing moderate to severe pain, a single oral dose of an aspirin/caffeine combination (800 mg aspirin, 65 mg caffeine) provided significantly more pain relief at 2 hours than did a higher dose of an acetaminophen/aspirin combination (648 mg acetaminophen, 648 mg aspirin) and a higher dose of acetaminophen alone (1000 mg acetaminophen). At 3 and 4 hours, the acetaminophen/aspirin combination as well as the aspirin/caffeine combination were significantly superior to acetaminophen alone. At all times, all three drugs were significantly superior to placebo. There were no clinically significant adverse reactions. These results provide evidence of a potentiating effect of caffeine on aspirin's analgesic potency. In two double-blind randomized, balanced, single oral dose studies with 140 women, a combination of 800 mg aspirin and 64 mg caffeine (aspirin-caffeine) was compared to 650 mg aspirin and to placebo. In patients with moderate to severe uterine or episiotomy pain, there was greater analgesic response with active drugs when the initial pain intensity was more severe. In patients with severe episiotomy pain, aspirin-caffeine was more effective than 650 mg aspirin (p less than 0.05) at the second and third hours. There was no difference between analgesic effects of aspirin and aspirin-caffeine in women with severe uterine pain. Caffeine is frequently added to mild analgesic preparations but its effect when used alone on pain has 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. Three hundred fifty outpatients with postoperative pain after the surgical removal of impacted third molars were randomly assigned, on a double-blind basis, to receive a single oral dose of aspirin 650 or 1000 mg, caffeine 65 mg, a combination of aspirin 650 mg with caffeine 65 mg, or placebo. Using a self-rating record, subjects rated their pain and its relief hourly for 6 hours after medicating. Estimates of summed pain intensity difference, peak pain intensity difference, total relief, peak relief, and hours of 50% relief were derived from these subjective reports. All active treatments except caffeine were significantly superior to placebo. Pairwise comparisons indicated the aspirin-caffeine combination was statistically superior to aspirin 650 mg alone for hours of 50% relief among patients who had severe baseline pain. Adverse effects were transitory and none were serious. We investigated efficacy, safety, and tolerability of two tablets of the fixed combination of 250 mg acetylsalicylic acid (ASA) + 200 mg paracetamol + 50 mg caffeine (Thomapyrin) in comparison with two tablets of 250 mg ASA + 200 mg paracetamol, two tablets of 500 mg ASA, two tablets of 500 mg paracetamol, two tablets of 50 mg caffeine, and placebo in patients who were used to treating their episodic tension-type headache or migraine attacks with non-prescription analgesics. For the primary endpoint "time to 50% pain relief" in the intention-to-treat dataset (n = 1743 patients), the fixed combination of ASA, paracetamol and caffeine was statistically significantly superior to the combination without caffeine (P = 0.0181), the mono-substances ASA (P = 0.0398), paracetamol (P = 0.0016), caffeine (P < 0.0001) and placebo (P < 0.0001). All active treatments except caffeine differed significantly (P < 0.0001) from placebo. The superior efficacy of the triple combination could also be shown for all secondary endpoints such as time until reduction of pain intensity to 10 mm, weighted sum of pain intensity difference (%SPIDweighted), extent of impairment of daily activities, global assessment of efficacy. All treatments were well tolerated. The incidence of adverse events observed was low. To compare the relative merits of single doses of ibuprofen and ibuprofen plus caffeine in the treatment of pain after third molar removal.
                Randomised, double-blind, placebo-controlled, single-dose parallel-group comparison of placebo, ibuprofen 200 and 400 mg with ibuprofen 200 mg plus 50, 100 or 200 mg of caffeine.
                161 patients undergoing lower third molar removal.
                All active treatments produced significant analgesia and mood elevation compared with placebo. There was no significant difference in the effects of 200 and 400 mg of ibuprofen. Adding caffeine to 200 mg ibuprofen produced significantly more analgesic effect at 45 and 60 min than ibuprofen 200 mg alone. Ten patients reported 11 adverse effects, none in the highest caffeine dose group.
                Caffeine increased the analgesic effect of ibuprofen 200 mg, through an earlier onset of analgesic effect. This was achieved in this single dose context without problematic adverse effects. Primary dysmenorrhoea is characterised by pain, cramping and backache at the time of menses. Despite the high prevalence of dysmenorrhoea, few sufficiently powered, placebo-controlled studies have examined the efficacy of over the counter analgesics in this condition. Furthermore, even fewer studies have directly examined the efficacy of analgesics on specific dysmenorrhoea symptoms. Research design and main outcome measures: This was a single-dose, placebo-controlled, double blind, crossover study carried out in 320 women with moderate-to-severe dysmenorrhoea pain. At 2 h following dosing, 1 g paracetamol plus 130 mg caffeine led to significantly greater pain relief compared to 1 g paracetamol alone (p < 0.05), 130 mg caffeine alone (p < 0.01) or placebo (p < 0.01). The combination was also significantly more effective in relieving abdominal cramping and backache compared to the other treatment arms. No major treatment related adverse events were reported during this study.
                When taken at recommended doses, both paracetamol and the combination of paracetamol and caffeine are safe and effective treatments for primary dysmenorrhoea. Consistent with results from other acute pain states, caffeine acts as an analgesic adjuvant and enhances the efficacy of paracetamol. A double-blind, randomized, single-dose study was performed to compare the efficacy and safety of two commonly prescribed combination analgesic products to placebo. The combinations were acetaminophen 300 mg/codeine 30 mg(†), and aspirin 325 mg/butalbital 50 mg/caffeine 40 mg/codeine 30 mg(††). One hundred twenty-three (123) oral surgery outpatients took study medications when their pain became moderate to severe and recorded the levels of pain intensity, pain relief, anxiety and relaxation at 30 minutes and hourly for 6 hours after dosing. Remedication was permitted if study medications did not provide adequate pain relief. Time to remedication, and the number of observations with 50% or better relief, were noted as were any side effects. An overall evaluation was obtained from each patient. Results of the study showed that the aspirin/butalbital/caffeine/codeine combination was significantly more effective than placebo for total pain relief, peak relief and global evaluation. While the acetaminophen/codeine combination was numerically superior to placebo, it achieved statistical significance only for global evaluation. The aspirin/butalbital/caffeine/codeine combination was numerically superior to acetaminophen/codeine for every measure of analgesic efficacy but the differences did not achieve statistical significance. Both active treatment groups experienced significantly less total anxiety than did the placebo group. Only 11 patients reported mild, transient adverse effects; the most common was drowsiness. The adverse effects occurred equally among the three treatment groups. In this study, the aspirin/butalbital/caffeine/codeine combination was significantly superior to placebo and somewhat better than acetaminophen/codeine.
The addition of caffeine (≥ 100 mg) to a standard dose of commonly used analgesics provides a small but important increase in the proportion of participants who experience a good level of pain relief.