Clinical support for the DISPRIN range of products
All references to Disprin in this section refer to soluble or mouth dispersible aspirin formulations.
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Pharmacokinetics |
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Clinical efficacy |
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Disprin Safety |
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Summary and benefits |
Pharmacokinetics
Acetylsalicylic acid, the active ingredient in Disprin soluble aspirin formulations, is an effective analgesic. However, as for all pain relievers, only by attaining an adequate plasma concentration will a satisfactory level of analgesia be reached. The formulation in which aspirin is administered is an important determinant of plasma levels and can, therefore, have a significant impact on both the speed of onset and the level of pain relief.
The size of the particles and the physical characteristics of the formulation determine the solubilisation rate of aspirin. For example, solid aspirin tablets are required to first disperse in the stomach and the aspirin particles thus released are then required to dissolve before absorption. These processes lead to a slow onset of pain relief.
Solubility
If aspirin is solubilised in water before dosing, this eliminates the gastric dispersion and dissolution steps in the absorption process and, thus, facilitates rapid absorption and, consequently, faster pain relief.
Hydrolysis and absorption
When aspirin is ingested, enzymes present in the gastric mucosa, blood and liver, begin to hydrolyse it to the less potent analgesic compound, salicylic acid. Since the aspirin in solid tablets is released relatively slowly in the stomach, significant quantities of aspirin are hydrolysed before absorption. However, because the aspirin from Disprin soluble formulations is presented to the stomach in solution, it is absorbed very rapidly and a ‘pulse’ of aspirin at high concentration is carried through the liver into the systemic circulation. The hydrolysing enzymes are overwhelmed and more aspirin is available systemically. The bioavailability of aspirin from Disprin is, therefore, higher than that from solid aspirin tablets.
Clinical evidence vs solid aspirin tablets
Several studies have shown that after taking Disprin soluble aspirin formulations the mean maximum concentration (Cmax) is significantly higher and the time taken to reach this point (Tmax) is reached significantly more quickly than with solid aspirin tablets.
In one study (Muir et al, Curr Med Res Opin 1997;13(10):547–553), volunteers received Disprin (2 x 300 mg) and solid aspirin (2 x 325 mg) in a within-subject crossover trial. Aspirin was not detected in all volunteers until 30–45 minutes after taking solid aspirin, yet within five minutes of Disprin administration, quantifiable levels of aspirin were found in the blood of every volunteer and within 20 minutes, Cmax had been reached.
Reproduced with kind permission from LibraPharm
Indeed, at the five minute time point, 15x more aspirin was found in patients after taking the soluble formulation, Disprin, than after taking the solid formulation. In addition, the total amount of aspirin available in the plasma was significantly higher from Disprin than from the solid tablet.
The rapidity of aspirin absorption was shown again in a second study (Muir et al, Curr Med Res Opin 1997;13(9): 491–500).Reproduced with kind permission from LibraPharm
The rapid relief from pain, inflammation and fever provided by Disprin is dependent on its ability to be rapidly and effectively absorbed. This property of soluble aspirin tablets has been shown in these, and many more clinical studies. The aspirin from Disprin can get into the bloodstream and get to work on pain in 5 minutes.
Summary: Disprin Pharmacokinetics vs Solid aspirin
Disprin's soluble aspirin formulations are preferable to solid aspirins because…
- significantly more aspirin is present in the blood within 5 minutes
- the aspirin level reached 5 to 10 minutes after dosing is higher than that achieved by solid aspirin at any time point
- the maximum aspirin concentration is significantly higher
- the maximum aspirin concentration is reached significantly more quickly
- the total amount of aspirin available per dose is significantly higher
…so Disprin soluble aspirin formulations give significant aspirin levels after only 5 minutes and reach maximum concentrations up to 3 times faster than solid aspirin.
Clinical evidence vs solid paracetamol tablets
One of the most widely used analgesics to treat mild to moderate pain is paracetamol. Like aspirin it is available in many formulations but the most widely used by far is the simple solid tablet. Studies have been conducted to compare the pharmacokinetics of soluble aspirin and solid paracetamol tablets.
Comparative pharmacokinetics
We know that soluble aspirin gets to work quicker than solid aspirin because it is already dissolved and available for absorption, but how does it compare with solid paracetamol tablets? Aspirin starts to be absorbed from the stomach, whereas paracetamol starts to be absorbed lower down the gastrointestinal tract, starting at the duodenum. This may delay its absorption, particularly in conditions, such as migraine headache, where gastric stasis may be a factor.
Very few comparative studies have been carried out to investigate the results of this difference, but one particular trial did look at the pharmacokinetics of solid and soluble paracetamol, solid aspirin and the soluble aspirin present in Disprin.
Speed of absorption vs solid paracetamol
Muir et al (Curr Med Res Opin 1997;13(9): 491–500) studied doses of two tablets (either soluble or solid), each containing 300 mg aspirin and 200 mg paracetamol in healthy, fasting volunteers. The uptake of aspirin and paracetamol from each tablet preparation was compared.
Since, in the soluble formulations, both drugs are already dissolved, they would be expected to be absorbed more quickly than the solid tablets, as the solid versions must first dissolve in the stomach before absorption can take place. When the paracetamol formulations were studied, the soluble formulation achieved maximum levels much faster than solid paracetamol tablets (40 minutes compared with 60 minutes). Similarly soluble aspirin was significantly more quickly absorbed than solid aspirin.
In addition, a highly significant advantage was seen in favour of soluble aspirin over solid paracetamol tablets in terms of the maximum concentration and the speed at which this is reached – at least 3 times faster (see histogram). This is because a rate-limiting step in the absorption of paracetamol is its clearance from the stomach.
Five minutes after dosing, no measurable paracetamol was present in the blood, whereas significant concentrations of aspirin were seen. At 10 minutes, aspirin concentrations were approaching their maximum and were 10 times higher than paracetamol concentrations.(Adapted from Muir et al Curr Med Res Opin 1997; 13 (9): 491-500)
Recently a study by Stillings et al (Curr Med Res Opin 2000;16(2): 115–124) reported the pharmacokinetics of Disprin soluble aspirin (900mg) compared with solid paracetamol tablets (1000mg) in fasted and fed volunteers. It concluded that aspirin was absorbed rapidly from Disprin in both fasted and fed individuals and that absorption of aspirin was largely unaffected by food. In contrast paracetamol absorption was significantly impaired by food to an extent where in some individuals maximum paracetamol levels did not attain those thought to be required for effective analgesia.
| Aspirin Fasted and Fed | ||
| Paracetamol Fasted and Fed | ||
Reproduced with kind permission from LibraPharm
Summary: Disprin pharmacokinetics vs ordinary solid paracetamol tablets
The aspirin in soluble forms such as Disprin is already dissolved and can immediately begin to be absorbed in the stomach, whereas solid paracetamol tablets must first dissolve in the stomach and then be transported to the duodenum before absorption can begin.
This means that:
- The aspirin in Disprin formulations is absorbed much more quickly than paracetamol from solid tablets
- Aspirin from Disprin formulations can reach maximum analgesic concentrations at least 3 times faster than paracetamol from ordinary solid tablets
- After 10 minutes, aspirin concentrations are approaching their maximum and are much higher than paracetamol concentrations
- aspirin absorption from Disprin is largely unaffected by food whereas absorption from ordinary solid paracetamol tablets is significantly affected
- Aspirin from Disprin formulations achieves a higher maximum analgesic concentration than paracetamol from ordinary solid tablets before or after food
Clinical efficacy
Aspirin is effective in alleviating pain, fever and inflammation because of its action on the synthesis of prostaglandins, which are responsible for many physiological functions.
The production of prostaglandins during trauma or illness is reduced by aspirin via its inhibition of cyclo-oxygenase – an essential enzyme involved in prostaglandin production. The pharmacokinetics of Disprin predict that it should act more rapidly and give a higher level of pain relief than solid aspirin. A number of studies have been carried out to confirm this.
Post Extraction Dental Pain
In a study of patients who underwent surgery to remove all four third molars, (Seymour RA, Hawkesford JE, Sykes J, Stillings M, Hill CM (2003. Br Dent J; 194 : 153-157) showed that patients taking 1.2 g Disprin reported a significant reduction in post-operative pain after only 15 minutes. In contrast, patients taking 1.2 g solid aspirin did not have a significant decrease in pain until one hour after dosing (see graph). In addition, a longer duration of effect was seen with Disprin.
Reproduced with kind permission from Springer-Verlag
In a second study, Holland and colleagues (Br J Clin Pharmacol, 1988;26:463–468) treated patients for acute inflammatory post-operative pain with both solid and soluble aspirin formulations, following the removal of impacted third molars. They found that patients taking three different doses of Disprin, up to 1.2 g, reported significantly less pain than placebo-treated patients, and that a dose-response effect was seen.
Reproduced with kind permission from Blackwell Science
The study also proved that, on a comparative dose basis, Disprin was significantly more effective than ordinary solid aspirin and, like the Seymour study, gave significant pain relief after only 15 minutes (Sykes et al Data on file, R&C, 1998) at dose levels of 900 and 1200 mg.
This finding is consistent with results from the pharmacokinetic studies, which suggested that more aspirin is absorbed more rapidly from Disprin than from solid tablets.
The
studies described above compare the clinical efficacy of Disprin versus
solid aspirin in post extraction dental pain. A further randomised, double-blind,
placebo-controlled study compared the efficacy of Disprin (900 mg) with
that of solid paracetamol tablets (1000 mg) in 167 patients who had their
impacted third molars removed under general anaesthetic (Seymour et al
submitted).
This study demonstrated that as early as 10 minutes after administration,
Disprin was significantly better than solid paracetamol in terms of pain
reduction, with some effect being detectable after 5 minutes. These results
support previous observations that aspirin from Disprin enters the blood
stream faster than paracetamol from solid tablets.
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After 20 minutes, patients taking Disprin reported significantly less pain than those given either solid paracetamol tablets (P = 0.035) or placebo (P = 0.028) and at this time, Disprin was twice as effective as solid paracetamol in terms of pain reduction. Over the entire 4-hour study period Disprin was superior to solid paracetamol in reducing pain.
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Due to its effects on platelet aggregation dentists often perceive that aspirin preparations will exacerbate gingival bleeding after dental surgery. In this study the incidence of gingival bleeding was similar in patients receiving Disprin or solid paracetamol tablets.
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These findings prove that Disprin can relieve dental pain in as little as 10 minutes without any increased incidence of gingival bleeding.
Orthopaedic and Surgical Pain
Disprin was preferred to solid aspirin by patients suffering from skeletal pain in a study by Dixit and colleagues (Acta Therapeutica 1984;10:333–340).
Patients were given 700 mg Disprin or solid aspirin to relieve orthopaedic or post-operative pain, which was recorded using a visual analogue scale. Pain scores showed that Disprin provided more effective and more rapid pain relief than solid aspirin.
These, and many more studies, provide clinical evidence of the superiority of soluble aspirin formulations, such as Disprin, over solid tablets in relieving pain, as predicted by the pharmacokinetic studies.
The effectiveness of Disprin has been clinically proven during half a century of use. It is quick to dissolve – leaving little residue, rapidly absorbed and fast-acting, beginning to relieve pain in as little as 15 minutes.Disprin has been proven to be fast-acting and effective in well-recognised models of pain, and soluble formulations should be the aspirin of choice for the fast relief of everyday aches and pains.
Migraine Headache
The rapid absorption of aspirin from Disprin predicts that it may be the analgesic of choice in acute migraine attacks. Disprin soluble aspirin products are particularly appropriate as initial absorption from the stomach may not be affected by gastric stasis, which is commonly associated with migraine. In addition, rapid inhibition of platelet aggregation may abort an attack during the early stages as platelets have been implicated in the initiation of migraine.
A small pilot study (Brandon et al., 1986) defined the role of both Disprin and Disprin Direct, a mouth dispersible aspirin formulation, in migraine. In this study, the medication was not taken at an early stage in an attack but when the headache was well established. The study also examined the absorption of aspirin in these patients.
The study was a randomised, parallel group study in 20 patients comparing the effects of Disprin 600mg and Disprin Direct 600mg. Both treatments were associated with significant decreases in pain compared with the starting value (p<0.01). There was no significant difference between treatments. Plasma level measurements clearly demonstrated that significant absorption occurred from both formulations
Significant absorption occurred from both formulations, with Disprin being absorbed faster than Disprin Direct.
Following on from these results a recent randomised, double-blind, placebo-controlled study (MacGregor et al, Headache (2002), 42 (4), 249 - 255) has evaluated the efficacy of Disprin Direct in 101 patients with established migraine headache, who would normally expect to experience a severe attack. In this study patients were given single doses of Disprin Direct (900 mg) or a matching mouth dispersible placebo to take in a randomised order to treat two moderate migraine headaches within 4 hours of onset.
The results demonstrated that Disprin Direct provided rapid and significant relief from migraine, with significantly more patients reporting almost complete relief within 2 hours of taken Disprin Direct, compared with placebo (48% versus 19%; p=0.0005; see figure). Significantly more patients responded to treatment at all time points after 30 minutes post treatment with Disprin Direct compared with placebo (p<0.05). In addition to a rapid response to treatment with Disprin Direct, significantly more pain relief was still reported by patients 6 hours after dosing with Disprin Direct compared with placebo.
The study also evaluated the number of patients that were completely pain free following treatment. Compared with placebo, significantly more patients receiving Disprin Direct were free from pain 3 hours after treatment (p<0.05; see figure) and significantly fewer required rescue medication after this time (p<0.01). Reduction in pain from baseline assessments was significantly greater from 30 minutes onwards following treatment with Disprin Direct compared with placebo (p<0.01).
As well as the pain associated with a migraine headache, sufferers also experience photophobia, phonophobia, nausea and significant functional disability, which sometimes severely impacts on their ability to perform everyday tasks. In this study Disprin Direct was superior with respect to relieving phonophobia, photophobia, nausea and functional disability (see figure).
The studies above show Disprin Direct to be an ideal analgesic for those patients who suffer from aspirin responsive migraine headache. The studies have been performed in migraine patients who are already experiencing moderately severe symptoms and who would expect to experience a severe attack. Many sufferers can identify their prodromal symptoms and if Disprin Direct is taken at this time migraine relief may be even greater than reported in these studies. Because Disprin Direct doesn't need to be taken with water it can be carried around and taken when the first signs of migraine appear to maximise symptom relief.
Length of Action
The studies on Disprin soluble aspirin formulations described in this section show quite clearly that the early onset of analgesia predicted by the pharmacokinetic studies is reflected in the clinical situation. However, the pharmacokinetic studies also suggest that the half-life of aspirin in the plasma is only about 20 minutes and that the molecule has disappeared from plasma in about 2 hours. Although this might suggest that the analgesic effect of Disprin would be short-lived; in fact the clinical studies reported here, and other data, clearly show analgesia is maintained for up to 5 hours following a single dose.
There are two possible factors that may explain the prolonged effects of aspirin. The first is the irreversible inhibition of the cyclo-oxygenase (COX) enzyme by aspirin. This results in prostaglandin synthesis being inhibited beyond the time (2 hours) that aspirin is present in the plasma. Only when cells are able to re-synthesise COX will prostaglandin production recommence and pain increase. A second factor that may prolong analgesia, particularly in inflammatory pain, is the efficient conversion of plasma aspirin into its metabolite salicylic acid. Although salicylic acid is a relatively weak inhibitor of COX-1, it does effectively block the inducible enzyme COX-2, which is key to the expression of inflammation. Salicylic acid is therefore an effective anti-inflammatory substance and its half-life of two hours is significantly longer than that of aspirin. Pharmacokinetic studies (Muir et al., 1983) have shown that salicylic acid levels rise quickly following administration of Disprin and are sustained for at least 5 hours.
Summary: Disprin clinical efficacy
Disprin soluble aspirin has been shown to be superior to ordinary solid aspirin in several clinical studies.
- A significant reduction in post-operative dental pain was seen only 15 minutes after taking Disprin.
- Dose for dose, Disprin was a more effective pain reliever than solid aspirin.
- Disprin has a longer lasting effect than solid aspirin.
- Patients with skeletal pain preferred Disprin to solid aspirin.
Disprin is faster acting, longer lasting and more effective than solid aspirin, and is effective in rapidly relieving mild-to-moderate pain.
Summary: Disprin Direct clinical efficacy
Disprin Direct has been shown to be superior to placebo in patients experiencing a moderate migraine attack.
- Disprin Direct can provide significant and long-lasting pain relief from migraine.
- Disprin Direct can relieve the pain of even severe migraine headache after 30 minutes.
- A single dose of Disprin Direct can go on working for at least 6 hours to relieve migraine.
- Disprin Direct can relieve the associated symptoms of photophobia, phonophobia, nausea and functional disability.
- Disprin Direct is palatable and convenient to use at the first signs of a migraine attack.
- Disprin Direct completely relieves the pain of migraine in many patients after 3 hours.
Disprin Safety
Gastric upset
Aspirin was developed from salicylic acid primarily to reduce the associated gastric side effects. However, some damage to the gastric mucosa does occur with aspirin use. There are two main mechanisms that cause this damage:
local/systemic effects, due to aspirin inhibiting the production of gastroprotective prostaglandins;
local irritant effects, due to the direct contact of aspirin particles with the gastric mucosa, causing local damage.
While the damage resulting from the inhibition of gastroprotective prostaglandins is largely unavoidable, the local irritant effect can be minimised by reducing the physical size of aspirin particles in contact with the gastric mucosa and by ensuring that the aspirin is quickly and effectively absorbed.
Disprin soluble aspirin tablets were formulated with these aims in mind, and have been shown to cause less local damage to the gastric mucosa than solid aspirin in several studies.
In a very early study ( Vining and Kersley BMJ 1957, 444-445) 180 patients with rheumatoid arthritis were given 3.2 g of solid aspirin per day, 45 of these patients found the aspirin to be 'intolerable'. These 45 aspirin intolerant patients were then transferred to Disprin 3.2 g and subsequently only 8 of these patients then complained of astric sensitivity, a reduction of 82%. A glycine containing aspirin formulation was also included in the study and this was also found to significantly reduce gastrointestinal sensitivity compared with the solid aspirin dose. This was the first demonstration that the hoped for reduction in gi side effects, which stimulated the formulation work on Disprin, was proven.
One investigation (Jaiswal et al IUPHAR 9th International Congress of Pharmacology, 1984) compared the effects of Disprin's soluble aspirin and solid aspirin on the gastric mucosa. This randomised, double-blind, crossover study in 30 volunteers involved visual inspection by gastroscopy at various time intervals after drug administration. The results showed that the mean gastric damage score for solid aspirin was significantly higher than that for Disprin (see figure).
This study clearly shows that Disprin causes significantly less gastric damage compared with that observed with ordinary solid aspirin formulations.
Summary: Disprin Gastric Tolerance
It has been shown that aspirin has been shown to cause local damage to the gastric mucosa by two actions:
- inhibition of gastroprotective prostaglandins
- direct contact of particles of solid aspirin
- any bleeding which results is exacerbated by the systemic anti-platelet effects of aspirin.
Since the aspirin in Disprin is already dissolved, only solubilised aspirin is present in the stomach, and this is quickly absorbed, so…
- the aspirin from Disprin is in contact with the gastric mucosa for only a short time, thus limiting the local damage caused,
- whereas, the aspirin from solid formulations is present in the stomach in large particles for a longer time, which causes significantly more local damage.
- for particularly sensitive patients combination Disprin products containing paracetamol are available, which are even gentler on the stomach.
Disprin soluble aspirin formulations can cause significantly less gastric damage than solid aspirin tablets
Aspirin and Reye's Syndrome
Many countries warn that aspirin should not be taken by children under the age of 12 or 16 with a fever, or in children with a current or recent viral illness such as influenza or chicken pox. This is because of the suspected link between the use of aspirin in children and the rare but potentially fatal disease, Reye’s Syndrome:
It occurs in children with a current or recent viral disease such as influenza or chicken pox; patients suffer from repeated vomiting, coma and seizures resulting from encephalopathy and fatty degeneration of the liver; mortality rate is between 20 and 50%. In the UK a paper by Hall in 1986 reported on data from South London and Belfast which showed a strong association between a "Reye’s score" and the likelihood of a patient having received an antipyretic, which was more likely to be aspirin than paracetamol; US studies appeared to confirm this link:
Since that time different countries have adopted different policies regarding aspirin use in children. In the UK, manufacturers removed Junior Aspirin from the market in 1986 and agreed to restrict its usage to children over the age of 12. In More recently the age limit has been raised to 16 years. In the US where data linked children up to the age of 16 with aspirin and Reye’s, the labelling specified that it should not be used in children under 16 who were suffering a viral infection. Interestingly, in France there was no restriction in usage of aspirin in children.
Despite these different approaches, the incidence of Reye’s Syndrome is now extremely small in all three countries compared with the peak incidences in the mid 1980s.
However the reduction while at first seeming to vindicate the withdrawal of aspirin from children in the UK and the US is complicated by the increasingly clear characterisation of Reye’s Syndrome: many cases are now known to be due to inherent metabolic disorders not related to the use of aspirin and not true Reye’s, a distinction which could not be made in the 1970s and 80s.
So the link between aspirin usage and Reye’s Syndrome is not yet established beyond doubt. However, the fact that there is a continuing doubt about a potential link makes it very unlikely that advice on the use of aspirin in children will change.
Aspirin and Asthma
The majority of patients tolerate aspirin and other NSAIDs well; asthmatics however are an exception. Some of them suffer from a special type of asthma called Aspirin-Induced Asthma, (AIA). The frequency among asthmatics is around 8%–20%. Some patients also appear to be sensitive to paracetamol but not to the same degree.
There are many theories, which help explain why aspirin and the NSAIDs provoke this response but one of the favourites to date is based on aspirin’s ability to inhibit cyclo-oxygenase.
Aspirin blocks the enzyme cyclo-oxygenase and this significantly reduces the synthesis of prostaglandins. A further potential result of this blockade however is to shunt the cascade of reactions into a leukotriene pathway and leukotrienes are known to induce bronchoconstriction. This theory would only be reasonable if AIA patients were particularly sensitive to leukotrienes and the evidence to date is controversial. Other theories are based on AIA patients having abnormal platelets, having abnormal thromboxane/prostaglandin ratios in the lung or even having had a chronic viral infection. Whatever the cause, asthmatic patients should be advised to avoid the use of NSAIDs unless they are under the guidance of a doctor and have taken aspirin before with no problem.
Summary and benefits
Reckitt launched Disprin over 50 years ago to provide a formulation of aspirin that caused less gastric irritation, and gave faster and more effective pain relief than solid aspirin tablets.
Aspirin is an effective analgesic but to be effective, adequate plasma levels must be attained. Soluble aspirin is absorbed more rapidly than solid aspirin or paracetamol because it is dissolved in water before administration. The aspirin is therefore presented to the mucosa in a form, which facilitates rapid absorption, thus potentially giving faster pain relief than solid dosage forms. The bioavailability of aspirin from soluble formulations is greater than from solid aspirin tablets.
Clinical evidence shows that Disprin produces significant levels of aspirin in the plasma after just 5 minutes and reaches a maximum in 15 to 20 minutes. Moreover, a greater amount of aspirin is absorbed, a higher plasma level is reached and the peak plasma level is reached more quickly than with solid aspirin. Disprin also acts as an excellent prodrug for the production of salicylic acid, which may contribute to sustained anti-inflammatory analgesic activity.
Food has little effect on the absorption of aspirin from Disprin soluble tablets but has a significant effect on paracetamol absorption from solid tablets.
Clinical trials in patients after dental surgery show that Disprin significantly reduces post-operative pain after only 15 minutes compared with up to an hour with solid aspirin. Disprin also has a longer duration of effect and provides more rapid and more effective pain relief in patients suffering musculo-skeletal pain. Soluble and mouth dispersible aspirin formulations such as Disprin and Disprin Direct should also be actively considered in the treatment of migraine and may be particularly useful if taken in the early stages of an attack.
The main disadvantage of aspirin is that it can cause irritation of the gastric mucosa both by a local effect and by inhibiting the synthesis of protective prostaglandins in the stomach. Several studies show that Disprin causes less local damage to the gastric mucosa than solid aspirin. This is due to the shorter contact time and the smaller particle size of Disprin, limiting the local irritation.
Although the solubility of Disprin's aspirin formulations results in asignificant reduction in gastrointestinal side effects compared with solid aspirin there will still be some people who will continue to be sensitive to the aspirin in Disprin formulations. It is for this reason that Disprin globally is not now solely associated with aspirin as the active. Increasingly, paracetamol is being used as an alternative pain relieving ingredient. For short term relief of aches and pains such as headache, sore throat and backache and the feverishness associated with colds and flu, paracetamol is an excellent alternative and it can be used with increased confidence in asthmatic patients and those with gi sensitivity to aspirin.