PERSPECTIVE
Speed, science and optimal pain relief bination products based on ibuprofen are highly effective in relieving acute dental pain, whereas single doses of aspirin- and paracetamolbased products are less efficacious (11). The situation seems to be similar when it comes to the treatment of headache. In a study involving patients with migraine headache, a single dose of 400 mg ibuprofen was more effective than a single dose of 1000 mg paracetamol or 1000 mg aspirin, using the outcome measure of a change in pain severity from initially moderate or severe to no worse than mild at 2 h (12).
Pain is a major global health problem. Six of the 11 most prevalent conditions worldwide are pain-related, with tension-type headache and migraine being the second and third most prevalent conditions (1). Pain also ranks high among the conditions that have the longest-lasting impact: five of the top 11 contributors to years lived with disability are pain-related (1). Pain is not only of concern if it is chronic. Studies of patients with acute postoperative pain show that high pain scores are associated with a lower quality of life, some 4 weeks after surgery (2). Higher pain scores during the postoperative period substantially impaired patients’ sleep, sexual function and ability to perform physical activities (3). Another study identified a direct relationship between higher average postoperative pain levels and patient dissatisfaction with their postoperative experience (4).
Measuring efficacy When evaluating the efficacy of analgesics, it is important to consider the patient’s view of meaningful pain relief. Patients want large reductions in pain, whether for acute or chronic pain (5), and good pain relief brings much better function and quality of life (6). For example, a retrospective analysis of patients with chronic back pain or fibromyalgia revealed that patients rated their treatment as successful if their pain was reduced by 50–70%, from a level of 5–10 on a visual analogue scale (total score 10) to below three (no more than mild pain) (7). This is in agreement with the finding that a ≥ 50% reduction in the pain associated with fibromyalgia or frequent migraine led to major improvements in quality of life (8,9). Data from acute pain studies confirm that pain relief by at least 50% is a reasonably sensitive outcome measure. When comparing the efficacy of single doses of over-the-counter (OTC) analgesics for the treatment of postoperative pain, the highest degree of discrimination between highly effective treatments was seen if the minimum efficacy criterion was pain relief by 50% or more (10). Use of this outcome measure (maximum pain relief ≥ 50% over 6 h) revealed that single doses of NSAIDs (ibuprofen, naproxen, diclofenac) and com-
Speed Successful pharmacological management of pain does not depend only on selecting an effective drug at the correct dose and balancing efficacy against adverse effects. The speed of onset of pain relief is also important – an aspect that is often overlooked. In a retrospective analysis of the use of ibuprofen for the treatment of dental pain, Laska et al. (13) showed that there is a clear relationship between the plasma concentration of ibuprofen at 1 h and pain intensity ratings. The proportion of patients with no or mild pain increased dramatically by serum concentration, to the extent that all patients with a 1-h serum concentration > 61 mg/l reported no or mild pain at 1 h. In addition, no patient with a serum level > 30 mg/l reported severe pain at 1 h, compared with more than a quarter of patients with a low serum level of ibuprofen (1–10 mg/l). This implies that fast-acting formulations provide considerable benefit over standard formulations. Ibuprofen is a relatively weak acid that does not dissolve well in the acidic environment of the stomach, slowing down plasma absorption. The process can be accelerated by using ibuprofen salts, which have a faster dissolution rate (14). Moore et al. (15) showed that standard formulations of ibuprofen as the free acid reach their peak plasma concentration at approximately 90 min, compared with < 50 min for fast-acting formulations in general and 29–35 min for the arginine, lysine and sodium salts of ibuprofen. This gain in time translates into meaningful pain relief being achieved almost 30 min earlier with the fast-acting formulations than with the standard for-
ª 2015 John Wiley & Sons Ltd Int J Clin Pract, May 2015, 69 (Suppl. 182), 21–23 doi: 10.1111/ijcp.12654
Rapid drug absorption leads to faster onset of pain relief, better overall pain relief, and a longer duration of pain relief
21
22
Perspective
mulation, as demonstrated in a systematic review of ibuprofen for the treatment of postoperative pain (15). In addition, the proportion of patients registering meaningful pain relief over a period of 6 h was consistently higher with the ibuprofen salts, meaning that fast-acting formulations do not only work faster, but they also provide better pain relief than standard formulations (15). An analysis of data from individual patients with dental pain further corroborates this view. There was a strong correlation (correlation coefficient 0.66) between a more rapid reduction of pain intensity over 0–60 min and better pain relief over 0–6 h (15). In agreement with these findings, pooled data from studies in dental pain indicate that patients taking a fast-acting formulation get good analgesia at half the dose required with a standard formulation (15) (Table 1). Further evidence for a link between rapid initial reduction in pain intensity and prolonged efficacy comes from studies assessing the need for remedication – a surrogate measure indicating the duration of effective analgesia before the pain intensifies again to the point where the patient requires an additional dose. In their systematic review of clinical trial data from over 10,000 patients and in analyses of individual patient data,
Moore et al. (15) showed that fast-acting formulations are consistently associated with a reduced need for remedication compared with same-dose standard formulations. These findings imply that drugs where the peak plasma concentration is reached sooner are likely to be more useful in clinical practice because they provide better and longer pain relief. By contrast, if the onset of pain relief is slow, the patient is likely to need more analgesia later on. This also has important implications for safety.
Food What are the practical implications of these observations in terms of taking NSAIDs with food? This practice is recommended in many countries. However, there is little evidence to support this approach, apart from studies in rodents, where fasting increased the gastric side effects of NSAIDs (16). When investigating the pharmacokinetic properties of a novel fixed-dose combination of ibuprofen and paracetamol, Tanner et al. (17) found that taking ibuprofen with food reduces the peak plasma concentration and delays absorption over the first hour (Table 2). This was also true for paracetamol. The back-transformed 90% CI for the peak plasma
Table 1 Number needed to treat (NNT) to achieve ≥ 50% pain relief over 6 h with a single dose of ibuprofen (indirect comparison of pooled data from studies in patients with dental pain) (15)
Formulation
Dose (mg)
Number of studies (n)
NNT (95% CI)
p-value
Standard Fast-acting Standard Fast-acting
200 200 400 400
16 7 42 10
2.9 2.1 2.4 1.8
Speed, science and optimal pain relief bination products based on ibuprofen are highly effective in relieving acute dental pain, whereas single doses of aspirin- and paracetamolbased products are less efficacious (11). The situation seems to be similar when it comes to the treatment of headache. In a study involving patients with migraine headache, a single dose of 400 mg ibuprofen was more effective than a single dose of 1000 mg paracetamol or 1000 mg aspirin, using the outcome measure of a change in pain severity from initially moderate or severe to no worse than mild at 2 h (12).
Pain is a major global health problem. Six of the 11 most prevalent conditions worldwide are pain-related, with tension-type headache and migraine being the second and third most prevalent conditions (1). Pain also ranks high among the conditions that have the longest-lasting impact: five of the top 11 contributors to years lived with disability are pain-related (1). Pain is not only of concern if it is chronic. Studies of patients with acute postoperative pain show that high pain scores are associated with a lower quality of life, some 4 weeks after surgery (2). Higher pain scores during the postoperative period substantially impaired patients’ sleep, sexual function and ability to perform physical activities (3). Another study identified a direct relationship between higher average postoperative pain levels and patient dissatisfaction with their postoperative experience (4).
Measuring efficacy When evaluating the efficacy of analgesics, it is important to consider the patient’s view of meaningful pain relief. Patients want large reductions in pain, whether for acute or chronic pain (5), and good pain relief brings much better function and quality of life (6). For example, a retrospective analysis of patients with chronic back pain or fibromyalgia revealed that patients rated their treatment as successful if their pain was reduced by 50–70%, from a level of 5–10 on a visual analogue scale (total score 10) to below three (no more than mild pain) (7). This is in agreement with the finding that a ≥ 50% reduction in the pain associated with fibromyalgia or frequent migraine led to major improvements in quality of life (8,9). Data from acute pain studies confirm that pain relief by at least 50% is a reasonably sensitive outcome measure. When comparing the efficacy of single doses of over-the-counter (OTC) analgesics for the treatment of postoperative pain, the highest degree of discrimination between highly effective treatments was seen if the minimum efficacy criterion was pain relief by 50% or more (10). Use of this outcome measure (maximum pain relief ≥ 50% over 6 h) revealed that single doses of NSAIDs (ibuprofen, naproxen, diclofenac) and com-
Speed Successful pharmacological management of pain does not depend only on selecting an effective drug at the correct dose and balancing efficacy against adverse effects. The speed of onset of pain relief is also important – an aspect that is often overlooked. In a retrospective analysis of the use of ibuprofen for the treatment of dental pain, Laska et al. (13) showed that there is a clear relationship between the plasma concentration of ibuprofen at 1 h and pain intensity ratings. The proportion of patients with no or mild pain increased dramatically by serum concentration, to the extent that all patients with a 1-h serum concentration > 61 mg/l reported no or mild pain at 1 h. In addition, no patient with a serum level > 30 mg/l reported severe pain at 1 h, compared with more than a quarter of patients with a low serum level of ibuprofen (1–10 mg/l). This implies that fast-acting formulations provide considerable benefit over standard formulations. Ibuprofen is a relatively weak acid that does not dissolve well in the acidic environment of the stomach, slowing down plasma absorption. The process can be accelerated by using ibuprofen salts, which have a faster dissolution rate (14). Moore et al. (15) showed that standard formulations of ibuprofen as the free acid reach their peak plasma concentration at approximately 90 min, compared with < 50 min for fast-acting formulations in general and 29–35 min for the arginine, lysine and sodium salts of ibuprofen. This gain in time translates into meaningful pain relief being achieved almost 30 min earlier with the fast-acting formulations than with the standard for-
ª 2015 John Wiley & Sons Ltd Int J Clin Pract, May 2015, 69 (Suppl. 182), 21–23 doi: 10.1111/ijcp.12654
Rapid drug absorption leads to faster onset of pain relief, better overall pain relief, and a longer duration of pain relief
21
22
Perspective
mulation, as demonstrated in a systematic review of ibuprofen for the treatment of postoperative pain (15). In addition, the proportion of patients registering meaningful pain relief over a period of 6 h was consistently higher with the ibuprofen salts, meaning that fast-acting formulations do not only work faster, but they also provide better pain relief than standard formulations (15). An analysis of data from individual patients with dental pain further corroborates this view. There was a strong correlation (correlation coefficient 0.66) between a more rapid reduction of pain intensity over 0–60 min and better pain relief over 0–6 h (15). In agreement with these findings, pooled data from studies in dental pain indicate that patients taking a fast-acting formulation get good analgesia at half the dose required with a standard formulation (15) (Table 1). Further evidence for a link between rapid initial reduction in pain intensity and prolonged efficacy comes from studies assessing the need for remedication – a surrogate measure indicating the duration of effective analgesia before the pain intensifies again to the point where the patient requires an additional dose. In their systematic review of clinical trial data from over 10,000 patients and in analyses of individual patient data,
Moore et al. (15) showed that fast-acting formulations are consistently associated with a reduced need for remedication compared with same-dose standard formulations. These findings imply that drugs where the peak plasma concentration is reached sooner are likely to be more useful in clinical practice because they provide better and longer pain relief. By contrast, if the onset of pain relief is slow, the patient is likely to need more analgesia later on. This also has important implications for safety.
Food What are the practical implications of these observations in terms of taking NSAIDs with food? This practice is recommended in many countries. However, there is little evidence to support this approach, apart from studies in rodents, where fasting increased the gastric side effects of NSAIDs (16). When investigating the pharmacokinetic properties of a novel fixed-dose combination of ibuprofen and paracetamol, Tanner et al. (17) found that taking ibuprofen with food reduces the peak plasma concentration and delays absorption over the first hour (Table 2). This was also true for paracetamol. The back-transformed 90% CI for the peak plasma
Table 1 Number needed to treat (NNT) to achieve ≥ 50% pain relief over 6 h with a single dose of ibuprofen (indirect comparison of pooled data from studies in patients with dental pain) (15)
Formulation
Dose (mg)
Number of studies (n)
NNT (95% CI)
p-value
Standard Fast-acting Standard Fast-acting
200 200 400 400
16 7 42 10
2.9 2.1 2.4 1.8
