To determine the best analgesic for postoperative pain management, three factors must be considered:
- The analgesic must be effective
- 2. The analgesic must be safe
- The analgesic must be cost-effective
Since NSAIDs are the mainstay treatment of mild to moderate intensity and are the first option to consider in the treatment of pain in outpatients, their effectiveness, safety and cost/effectiveness are reviewed below.
1. Evaluation of effectiveness.
Effectiveness means that the medicine must produce significant pain relief. That is, it must be a good analgesic. The efficacy of a drug is measured by the number needed to treat (NNT). The ideal anaesthetic should have an NNT. This means that each subject receiving the drug reports adequate analgesia. The meta-analyses that evaluate the effectiveness of analgesics define “adequate analgesia” as pain relief of at least 50%. Although a minor decrease (35%), it is considered by patients as a “significant relief” if the pain is of moderate intensity.
How effective are NSAIDs?
The NNT of NSAIDs is small, indicating that they are suitable analgesics. The NNT of 1 g of acetaminophen is 3.6, with a 95% confidence interval (CI) of (3.0-4.5). This means that four patients must be treated for one patient to obtain a 50% decrease in pain. The NNT of ibuprofen (400 mg) is 2.3 [95% CI 2-3.6]. Diclofenac (50 mg) , dipyrone, piroxicam and ketorolac are as effective as ibuprofen 400 mg.
NSAIDs vary in their anti-inflammatory effect, and this may be desirable in some clinical circumstances. Acetaminophen has a weak anti-inflammatory action. Contrary to popular belief, dipyrone has a potent inhibitory effect on cyclooxygenase in the periphery. However, in vivo, its anti-inflammatory effect appears less intense than traditional NSAIDs.
2. Security evaluation.
The ideal pain reliever should be practical and also safe. The risk of a severe adverse effect when an individual is exposed to an NSAID is 1.38%. The most common side effects are:
- Risk of bleeding at the surgical site: 1.04%.
- Risk of gastrointestinal bleeding: 0.04% to 1%.
- Risk of allergic reactions: 0.12%.
- Risk of kidney failure: 0.09%.
- Risk of death: 0.17%.
Is one NSAID safer than another?
Some NSAIDs are safer than others. Pharmacovigilance studies and randomised multicenter studies have shown that acetaminophen, followed by ibuprofen and then dipyrone is the safest NSAID. For example, with diclofenac, there is a 23 times higher risk of developing adverse effects than with acetaminophen. The fear of morbidity and mortality due to agranulocytosis with dipyrone is exaggerated. The risk of agranulocytosis associated with dipyrone is shallow (6.6 per million), and the risk is not particular to dipyrone. It is also associated with other NSAIDs. Comparing adverse effects overall, for dipyrone to be less safe than diclofenac, dipyrone would have to increase the risk of agranulocytosis by 300%.
Although oxicames seem to be associated with a higher incidence of gastrointestinal events than other NSAIDs, there is controversy since some studies have not found differences between oximes and traditional NSAIDs. Factors such as greater adherence to treatment, given its long half-life, or reporting bias, could explain the safety differences found in the studies.
No difference in safety has been seen between ketorolac, diclofenac and ketoprofen. It is important to emphasise that ketorolac should not be administered for more than five days.
3. Cost/effectiveness evaluation.
Once the effectiveness and safety of the different NSAIDs have been determined, it is necessary to decide which is the best analgesic. The third requirement that the ideal anaesthetic must meet is that it be cost-effective. This means that if two pain relievers are equally effective and safe, there is no doubt that we should choose the less expensive one. Given their effectiveness, safety, and cost/effectiveness ratio, acetaminophen, ibuprofen, and dipyrone are the best therapeutic options for outpatient post-surgical pain management.
4. What is the role of NSAIDs in selective inhibitors of cyclooxygenase 2?
Effectiveness: these NSAIDs are adequate; the NNT of rofecoxib 50 mg is 2.3 [95% CI 2.0-2.6].
Safety: NSAIDs that selectively inhibit cyclooxygenase 2 (COX-2) would theoretically have a lower incidence of side effects since synthesizing prostaglandins with physiological action is not hampered. But the safety advantage of these NSAIDs is limited to reducing gastrointestinal side effects. The degree of selectivity to inhibit COX-2 is only one of the many factors determining the development of adverse gastrointestinal effects. The plasma half-life and the degree of enterohepatic circulation of the NSAID are factors that contribute significantly to the occurrence of gastrointestinal complications.
Nabumetone, meloxicam and rofecoxib are associated with decreased gastrointestinal side effects. However, these findings cannot be generalized to all selective COX-2 inhibitors. The risk of gastrointestinal adverse events with some of these NSAIDs may be similar to that of traditional NSAIDs.
It is important to emphasize that selective COX-2 inhibitors, like traditional NSAIDs, except acetaminophen, should not be administered to patients with a history of the acid peptic disease, as they can interfere with the healing process of ulcers in the digestive system.
Cost/effectiveness: COX-2 selective NSAIDs are not cost/effective. There are equally effective, safe and cheaper options, such as acetaminophen. If an anti-inflammatory effect is desired in a population at high risk of developing gastrointestinal adverse effects, as in elderly patients, selective COX-2 inhibitors could have a role. However, formal cost/effectiveness studies should be carried out since it is not clear that these are more cost/effective, although the incidence of gastrointestinal adverse effects increases in subjects over 60 years of age. In addition, it is important to note:
- The decrease in gastrointestinal adverse effects could only be short-term (6 months)
- There is less experience with these NSAIDs, the number of subjects exposed to these drugs is limited, and a follow-up time of no more than six months to one year;
- Chronic use could be associated with an increased risk of cardiovascular thrombotic effects.
5. What to do if the pain persists or is expected to be severely intense?
If the pain persists despite the use of NSAIDs or the severity of pain expected after the surgical procedure is very intense, NSAIDs may be insufficient to produce adequate analgesia. In these circumstances, the dose of the NSAID should not be increased above the recommended dose since it increases the risk of developing gastrointestinal adverse effects up to 8 times. No other NSAID should be given either. NSAIDs have a “ceiling effect” for analgesia. Therefore more excellent pain relief is not obtained, but they do not have a “ceiling effect” for adverse effects. Administering more than one NSAID simultaneously increases the risk of gastrointestinal side effects from 2 to 23 times. In these cases, a weak opioid such as codeine or tramadol can be associated.
The association of acetaminophen with a weak opioid provides more excellent pain relief than each component. However, there is a higher incidence of side effects than when acetaminophen is administered alone. The number-needed-to-harm (NNH) is a measure similar to the number-needed-to-treat that measures the safety of a drug. Contrary to NNT, the larger the NNH value, the safer the drug. When tramadol 75 mg is associated with acetaminophen 650 mg, the NNH for vomiting is 5.7 [95% CI 4.3-8.5]. When codeine is added to acetaminophen, the NNH for drowsiness is 11 [95% CI 7.5-12.0]. This means that out of eleven patients to whom codeine is added to acetaminophen, one of them develops drowsiness.
If pain persists despite the addition of a weak opioid, more potent pure opioid agonists such as morphine, hydromorphone, or oxycodone should be considered. These analgesics have an NNT of 2.9 [95% CI 2.6-3.6]. The opioids mentioned, except oxycodone and controlled-release morphine, are cost-effective since, in addition to being excellent analgesics in our environment, they are cheaper than NSAIDs. The most common side effects of these opioids in outpatients are nausea, vomiting, and dizziness.
6. Conclusion:
To determine which analgesics are the best option, effectiveness, safety, and cost/effectiveness should be considered. Using these criteria, acetaminophen, ibuprofen, and dipyrone are the analgesics of choice in outpatients.