Caffeine and Headache: Relationship with the Effects of Caffeine on Cerebral Blood Flow
Caffeine is the most widely used psychoactive substance in the world. Most of the caffeine consumed comes from dietary sources such as coffee, tea, cola drinks, and chocolate. The consumption of caffeine is most often correlated with the positive effects following its ingestion, namely increased alertness, energy, and ability to concentrate (Benowitz, 1990; Fredholm et al., 1999; Nawrot et al., 2003). In addition to its dietary use, caffeine can also be found in a number of medications, mainly in over-the-counter and prescription preparations for weight loss and pain relief. The use of caffeine as an adjunctive constituent of analgesic medications can be dated back to 1875 when caffeine was first isolated and characterized structurally (Arnaud, 1987).
The first clinical trials concerning the possible contribution of caffeine to the analgesic properties of aspirin and acetaminophen were only performed at the beginning of the second part of the 20th century. However, the interpretation of these studies is rendered difficult by their methodological limitations (Beaver, 1966, 1981).
More recent, well-conducted studies have focused on the association of caffeine, mainly with aspirin or acetaminophen, and the contribution of caffeine to the antipain efficacy of analgesics in migraine and tension-type headache. In 1988, the FDA classified caffeine as belonging to Category I ingredients considered to be “generally regarded as safe and effective” and to Category III ingredients considered as requiring additional research to prove efficacy as over-the-counter anal
gesic adjuvants (Beaver, 1981; FDA, 1988). In 1994, a review on caffeine data by the Nonprescription Drugs Advisory Committee reported that a 130-mg caffeine dose provided significant adjuvant efficacy when combined with aspirin or acetaminophen/aspirin in a variety of pain states (Dalessio, 1994). The combination of caffeine with current prescription and nonprescription drugs in alleviating migraine and tension-type headache-related symptoms and pain has been the subject of a number of studies that will be summarized below. These studies are of clinical importance since most approved prescription drugs for headache, mainly migraine, are expensive and many have therapy-limiting side effects and contraindications (Von Seggern, 1992; Solomon, 1993; Kumar and Cooney, 1995).
ANTINOCICEPTIVE PROPERTIES OF CAFFEINE
As reviewed here, most of the actions of caffeine reflect its action as a nonspecific antagonist at adenosine receptors (Nehlig et al., 1992; Fredholm et al., 1999). Among its numerous pharmacological effects on the body, caffeine has been reported to express intrinsic antinociceptive actions in animal models (Daly, 1993); however, they depend on the type of pain stimulus: mechanical, thermal, or electrical (Seegers et al., 1981; Person et al., 1985; Castaneda- Hernandez et al., 1994; Engelhardt et al., 1997; Diaz-Reval et al., 2001). Only rare human studies have assessed whether caffeine alone has independent analgesic properties. In two studies including 301 and 53 subjects suffering from tension-type headache, caffeine significantly relieved pain in a dose-dependent manner (Ward et al., 1991; Diamond et al., 2000). The antinociceptive actions of caffeine are considered to be linked to its antagonism at the level of adenosine receptors. In the peripheral nervous system, adenosine A1 receptor activation produces antinociceptive actions by decreasing, while adenosine A2 receptor activation produces pronociceptive or pain-enhancing properties by increasing cyclic AMP levels in the sensory nerve terminals.
Adenosine A3 receptor activation produces pain behaviors due to the release of histamine and serotonin from mast cells and subsequent actions on nerve cell terminals. In humans, the peripheral administration of adenosine produces pain responses resembling those generated under ischemic conditions (Sawynok, 1995, 1998). Thus, adenosine systems appear to contribute to the antinociceptive properties of caffeine. Antinociception results from the inhibition of intrinsic neurons by an increase in K+ conductance and presynaptic inhibition of sensory nerve terminals to inhibit the release of substance P and glutamate with subsequent actions on pain perception (Sawynok and Yaksh, 1993; Sawynok, 1998) . The intrinsic antinociceptive actions of caffeine have been proposed to result from actions at supraspinal sites because manipulation of central monoaminergic pathways can inhibit such actions (Sawynok and Reid, 1996) and may involve inhibition of presynaptic adenosine receptors on cholinergic nerve terminals (Ghelardini et al., 1997). In addition, during headaches, adenosine receptor-mediated vasodilation and/or irregular vascular tone contribute to pain (Dalessio, 1979; Ferrari, 1991).
A number of studies have addressed the question of the adjunctive analgesic properties of caffeine in over-the-counter and prescription pain medications for both headache and other types of pain. For example, 65 to 100 mg of caffeine potentiate the analgesic effects of 500 mg of acetaminophen or 200 mg of ibuprofen in postpartum uterine cramping (Jain et al., 1978; Laska et al., 1983, 1984; Akin et al., 1996), postpartum pain and episiotomy (Laska et al., 1983, 1984), third molar extraction (Laska et al., 1983; Forbes et al., 1991; McQuay et al., 1996), and dentoal- veolar pain (Kiersch and Minic, 2002). Based on a pooled analysis of 30 clinical studies including about 10,000 patients suffering from various types of pain, including headaches, Laska et al. (1983, 1984) estimated that the combination of caffeine with current analgesics has a potency of 1.41, which means that it would take 41% more aspirin or acetaminophen alone to reach the same analgesic level as the combined medication.
EFFICACY OF CAFFEINE IN THE TREATMENT OF TENSION-TYPE HEADACHES
Tension-type headaches, as classified by the International Headache Society (1988), occur usually at a maximal frequency of 15 per month and respond to nonprescription medications. They are most often not accompanied by disabling pain and work arrest (Jensen and Paiva, 1993; Matthew, 1993) . In the studies detailed below, the patients recruited experienced between four and ten tension- type headaches per month during the year preceding the study (International Headache Society, 1988) . In tension-type headaches, the efficacy of the combination of caffeine with acetaminophen and aspirin has been repeatedly reported (Laska et al., 1984; Schachtel et al., 1991; Migliardi et al., 1994; Diamond et al., 2000).
In a randomized, double-blind, parallel-design trial, Schachtel et al. (1991) compared the analgesic properties of a single dose of acetaminophen (1000 mg) or aspirin (1000 mg) with caffeine (64 mg) or placebo in 302 subjects with tension-type headache. Acetaminophen and the combination of aspirin with caffeine were significantly more efficient than placebo in terms of the sum of pain intensity difference from baseline, total pain relief, and percentage of patients experiencing total pain relief. The aspirin/caffeine combination was rated superior to acetaminophen alone for the sum of pain intensity difference from baseline and percentage of patients experiencing complete pain relief.
In a series of six randomized, double-blind, two-period crossover studies, conducted under similar protocols, Migliardi et al. (1994) compared the analgesic efficacy of two combinations containing caffeine in subjects with tension-type headache. In the first four studies involving 1900 patients, tablets of acetaminophen (500 mg), aspirin (500 mg), and caffeine (130 mg) (APAP/ASA/CAF) were combined, while in two other studies involving 911 subjects, two tablets of acetaminophen (1000 mg) and caffeine (130 mg) (APAP/CAF) were combined. The patients were all involved in two treatment periods during which they took two separate medications for two different headache attacks. Acetaminophen was found superior to placebo, but the APAP/CAF and APAP/ASA/CAF combinations were significantly superior to acetaminophen alone and placebo. The caffeine adjuvant effect reached 76% for sum of pain intensity difference from baseline, 89% for percentage of pain intensity difference from baseline, and 97% for total pain relief. For peak analgesia and duration, the caffeine adjuvant effect of the two combinations compared to acetaminophen alone ranged from 63 to 85%. The pooled analgesic responses for the four studies of APAP/ASA/CAF and the two studies of APAP/CAF were virtually superimposable. The effect of caffeine in this antipain medication was totally independent of the usual dietary caffeine intake of the patients or their caffeine consumption in the 4 h preceding medication. However, the two combinations produced more stomach discomfort, nervousness, and dizziness than acetaminophen or placebo (Migliardi et al., 1994).
More recently, in a randomized, double-blind, multicenter trial, Diamond et al. (2000) compared the analgesic effect of ibuprofen alone (400 mg), ibuprofen (400 mg) plus caffeine (200 mg), caffeine alone (200 mg), or placebo in 301 subjects with tension-type headache. The combination of ibuprofen and caffeine provided significantly greater analgesic effects than ibuprofen alone, caffeine alone, or placebo. This was true for the delay between the medication and meaningful improvement in headache relief, total analgesia provided over 4 and 6 h, peak relief, and the number of patients reporting these improvements. This study also showed a similar efficacy of caffeine (200 mg) or ibuprofen (400 mg) alone (Diamond et al., 2000), which is in line with the data of an older study reporting a similar efficacy of caffeine (65 or 130 mg) or acetaminophen (650 mg) alone in the treatment of tension-type headache (Ward et al., 1991).
The analgesic potency of caffeine alone was also shown in another type of headache, postdural puncture headache. The addition of caffeine to saline during the first 90 min after spinal anesthesia reduced moderate and severe postdural puncture headaches as well as the analgesic demand for 4 d. In these cases, caffeine was found to be a simple and safe way to minimize postdural puncture headache (Ford et al., 1989; Yucel et al., 1999; Vincent and Aboff, 2001).
In conclusion, in tension-type headaches, caffeine has both analgesic properties by itself and appears to be able to potentiate the analgesic properties of common antipain drugs such as acetaminophen, aspirin, and ibuprofen.
EFFICACY OF CAFFEINE IN THE TREATMENT OF MIGRAINE HEADACHES
Migraine is a recurrent disorder that produces a wide spectrum of pain and disability (Stewart et al., 1996a; Von Korff et al., 1998). An estimated 23 to 25 million Americans, 18% of women and 6% of men, suffer from migraine attacks (Stewart et al., 1992), among whom more than 50% experience at least one episode per month (Rasmussen and Olesen, 1993). Only 5 to 15% of migraine attacks are associated with mild pain and no disability; moderate to severe pain and disability are reported in 60 to 70% of attacks, and incapacitating pain, bed rest, and total disability occur in 25 to 35% of the attacks (Lipton and Stewart, 1993; Von Korff et al., 1994; Stewart et al., 1996b). The severity of the attacks is variable in a given person (Johannes et al., 1995; Von Korff et al., 1998). Most migraine sufferers (65% of men and 57% of women) manage their headache with nonprescription medications (Celentano et al., 1992), but it is not clear how effective these medications are in the treatment of severe migraine attacks. Indeed, the optimal treatment depends both on the severity of the disease and the severity of individual attacks (Lipton et al., 1994; Michel et al., 1997; Pryse-Phillips et al., 1997; Lipton, 1998).
In a series of three double-blind, randomized, parallel-group, single-dose, placebo-controlled trials, Lipton et al. (1998) examined the efficacy of the treatment of migraine symptoms in a population of 1220 subjects by a nonprescription combination of acetaminophen (500 mg), aspirin (500 mg), and caffeine (65 mg) taken orally as a single-dose treatment. Significantly greater reductions in pain intensity were seen from 1 to 6 h after treatment in patients taking the medication compared to the placebo group. The percentage of patients free of pain at 6 h was twice as high in the medication group as in the placebo group. The other symptoms of migraine, such as nausea, photophobia, phonophobia, and functional disability, were significantly improved in the medicated compared with the placebo group. Goldstein et al. (1999) extended the analysis of the studies performed by Lipton et al. (1998) to a subgroup of 172 subjects, within the initial group of 1220, that were suffering from severe, disabling migraine symptoms. They reached conclusions similar to those in the study including the whole population of migraineurs and showed the superiority of the combination of acetaminophen, aspirin, and caffeine over the placebo in alleviating pain and associated symptoms in this group of patients more severely disabled by their migraines. Finally, the conclusions of the two previous studies were extended to menstruation-associated migraine in a group of 967 women extracted from the initial group of 1220 subjects. A similar efficacy of the combination of the medications cited above was also found in the case of menstruation-associated migraine (Silberstein et al., 1999).
However, in the three studies cited above, the objective was to analyze whether over-the-counter, rather inexpensive, medication could be effective in reducing migraine-associated pain and symptoms. The data of the three studies (Lipton et al., 1998; Goldstein et al., 1999; Silberstein et al.,
1999) confirm the safety and efficacy of the acetaminophen/aspirin/caffeine combination on migraine symptoms but do not outline the specific role of caffeine in this combination, since no comparison was performed with combinations containing or not containing caffeine or with caffeine alone. In fact, the efficacy of the acetaminophen/aspirin/caffeine combination was postulated by Strong (1997) to be possibly linked to the presence of caffeine; however, this hypothesis is based on the observation of only one case, the author of the paper himself (Strong, 1997). He found that only the combination of medication including caffeine and caffeine alone (100 mg) were effective in his migraine attacks. However, a large-scale study is still missing to clearly outline the potentiation of analgesic properties afforded by the addition of caffeine to an analgesic drug or combination of drugs as well as the efficacy of caffeine alone in the relief of pain and other symptoms associated with migraine.
More recent randomized, double-blind, multicenter, parallel-group studies also tested the efficacy of ergotamine (1 or 2 mg) plus caffeine (100 or 200 mg) vs. calcium carbasalate/lysine acetylsalicylate (equivalent to 900 mg of aspirin) plus metoclopramide (10 mg), eletriptan (80 mg), or rizatriptan (10 mg) in migraine. In the four studies, the mixture of aspirin equivalents and metoclopramide (Le Jeunne et al., 1999; Titus et al., 2000) and the serotonin receptor agonists eletriptan (Diener et al., 2002) and rizatriptan (Christie et al., 2003) were superior to the combination of ergotamine and caffeine in alleviating all migraine-associated symptoms, such as intensity of pain, duration of pain relief, nausea, photophobia, phonophobia, and functional disability.
Recently, Geyde (2001) published his hypothesized treatment for migraines. He is proposing to use a combination of products that would act on a whole subset of physiological regulations that are impaired during migraine attacks. Migraine attacks include, but are not limited to, (1) falling blood levels of serotonin (Anthony and Lance, 1971, 1989); (2) vascular dilatation (Dalessio, 1979; Ferrari, 1991); (3) inflammatory response in intracranial structures (Pearce, 1993), and (4) in some, but not all migraines, an increasing release of the vasodilator histamine (Guyton, 1991), which continues to rise 24 h after onset (Anthony and Lance, 1971). The author is proposing to use the following combination: (1) tryptophan (500 mg) as a precursor of serotonin; (2) niacin (nicotinic acid, 100 mg) to facilitate tryptophan’s conversion to serotonin; (3) acetylsalicylic acid (650 mg) to enhance tryptophan’s conversion to serotonin and reduce prostaglandin-mediated inflammation; (4) calcium carbonate (500 mg) (Guyton, 1991), and (5) caffeine (64 mg) to reduce vasodilation (Leonard et al., 1987). This treatment was tested on 12 subjects, 9 of whom were relieved from migraine symptoms within 1 h after taking the treatment.
CAFFEINE WITHDRAWAL HEADACHES
In sensitive individuals, caffeine withdrawal typically induces headaches, among other symptoms (Griffiths et al., 1990; Nehlig et al., 1992; Silverman et al., 1992; Hughes et al., 1993). A strong positive correlation has also been described between caffeine consumption, fasting, and headaches before and after surgical procedures. For every increase in the usual daily consumption of 100 mg of caffeine (about a cup of coffee), the risk of headache immediately before and after surgery is increased by 12 and 16%, respectively, and correlates also with the duration of fasting (Fennelly et al., 1991; Nikolajsen et al., 1994). The risk of headaches is reduced in individuals who drink caffeine or receive substitutive caffeine tablets on the day of the surgery (Weber et al., 1993, 1997; Hampl et al., 1995). Therefore, it was advised by three studies that the numerous healthy patients who drink caffeine-containing beverages daily and are undergoing minor surgical procedures should be permitted to ingest preoperative caffeine (Weber et al., 1993, 1997; Nikolajsen et al., 1994).
Caffeine withdrawal symptoms disappear soon after absorption of caffeine. This effect is strongly linked to the psychological satisfaction related to the ingestion of caffeine; this is especially true for the first cup of the day. The potential reversal of caffeine withdrawal-induced headache and other symptoms by the absorption of caffeine alone has been known for over 50 years and shown repeatedly (Dreisbach and Pfeiffer, 1943; Goldstein and Kaizer, 1969; Goldstein et al., 1969; Griffiths and Woodson, 1988; Hughes et al., 1991). The occurrence of headaches on substitution of caffeinated by decaffeinated coffee predicts subsequent caffeine self-administration (Hughes et al., 1991).
VASCULAR CHANGES DURING VARIOUS TYPES OF HEADACHES
Tension-type headaches are not accompanied by vascular changes (Andersson et al., 1997; Diener, 1997; Sliwka et al., 2001). Conversely, migraine attacks and the interictal state are characterized by cerebral blood flow changes, but there is no real consensus on the nature of the cerebrovascular changes in migraine states. In the interictal state, cerebral blood flow and baseline flow velocity were reported to be higher (Facco et al., 1996; Valikovics et al., 1996; Vasudeva et al., 2003), similar (De Benedittis et al., 1999), or lower (De Benedittis et al., 1999) in migraine patients compared to the control population. There were also differences between migraines with or without aura characterized by different, even opposite, deviations in regional cerebral blood flow (Facco et al., 1996; De Benedittis et al., 1999). During migraine attacks, most often reports indicate a decrease in regional cerebral blood flow (La Spina et al., 1994, 1997; Andersson et al., 1997; Cutrer et al., 1998; De Benedittis et al., 1999; Sanchez del Rio et al., 1999) or no change in migraine with aura (Silvestrini et al., 1996). In migraine without aura, the reports indicate no change (Ferrari et al., 1995; Thomsen et al., 1995; Silvestrini et al., 1996) or a reduction in cerebrovascular reactivity and cerebral blood flow (Andersson et al., 1997; Bednarczyk et al., 1998). Moreover, sumatriptan, a serotonin receptor agonist commonly used for the treatment of migraine headache, does not change cerebral blood flow during migraine attacks (Ferrari et al., 1995; Limmroth et al., 1996).
Conversely, there is a relationship between caffeine withdrawal, the development of headaches, and changes in cerebral blood flow. The cerebral blood flow velocities are increased during withdrawal headaches, significantly decrease within 30 min after caffeine intake in all subjects, and return to baseline values after 2 h (Couturier et al., 1997). This study is in line with others suggesting that increased blood volume may be involved in caffeine withdrawal headache (Dreisbach and Pfeiffer, 1943; Von Borstel et al., 1983; Hirsch, 1984; Mathew and Wilson, 1985b).
CEREBRAL VASOCONSTRICTIVE PROPERTIES OF CAFFEINE
Methylxanthines such as caffeine or theophylline induce vasodilation, except in the central nervous system, where they raise cerebrovascular resistance; this actually contributes to a reduction in cerebral blood flow. The vasoconstrictive properties of methylxanthines have been demonstrated in humans (Wechsler et al., 1950; Shenkin, 1951; Moyer et al., 1952; Gottstein and Paulson, 1972; Magnussen and Hoedt-Rasmussen, 1977; Mathew et al., 1983; Mathew and Wilson, 1985b, 1990; Cameron et al., 1990) and in animals (Oberdorster et al., 1975; Morii et al., 1983; Grome and Stefanovich, 1985, 1986; Puiroud et al., 1988; Ko et al., 1990; Nehlig et al., 1990). The absorption of 250 mg of caffeine in humans induces a decrease in cerebral blood flow ranging from 20 to 30% (Mathew et al., 1983; Mathew and Wilson, 1985b, 1990). This decrease is independent from mood, peripheric physiological activity, and arterial partial pressure of CO2 (Mathew et al., 1983; Mathew and Wilson, 1985a,b, 1990). Caffeine induces a regional decrease in cerebral blood flow, mainly in the areas where it increases metabolism (i.e., in monoaminergic cell groupings, in the motor and limbic systems, and in the thalamus) (Grome and Stefanovich, 1985, 1986; Nehlig et al., 1990).
At this point, the efficacy of caffeine in relieving headache induced by caffeine withdrawal, which leads to cerebral vasodilatation, appears clear and seems to reflect the central vasoconstrictive properties of the methylxanthine. In tension-type headache, there do not seem to be vascular changes related to the attack, and therefore the analgesic effect of caffeine per se or combined with other antipain medication is most likely mediated by other phenomena. It cannot be totally discounted, however, that the vasoconstrictive effect of caffeine could add to the mechanisms involved in pain relief. Finally, for migraine attacks, the literature is rather in favor of a decrease in cerebral blood flow during the attacks. The origin of pain in this pathology remains to be clearly defined; pain is attributed to the dilatation of the ipsilateral medial cerebral artery and also to the dilatation and increased pulsations of the superficial temporal artery and other extracranial arteries (Olesen, 1993). The role of caffeine in pain relief in migraine is not clearly understood and has not been fully
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