Efficacy of OTC analgesics.

For many 'over-the-counter' (OTC) analgesics, there is little information available about their relative efficacy. We have examined information available in a series of Cochrane reviews of single doses of analgesic drugs in acute pain and migraine for its relevance for analgesic products commonly available without prescription, at doses generally equivalent to two tablets. Pain following third molar extraction was used as a homogeneous acute pain model; with the outcome of at least 50% maximum pain relief over 6 h. For many OTC drugs, there was no information available. For some OTC drugs, there was at least some information available either for the marketed product itself, or from studies that used the same doses of drug or drugs. For acute pain, data from third molar extraction studies showed that several OTC products were highly efficacious, principally non-steroidal anti-inflammatory drugs (ibuprofen, naproxen, diclofenac) and combination products based on ibuprofen; aspirin and paracetamol-based products were less efficacious. Fixed-dose combinations, especially those with ibuprofen, provided high levels of analgesia. For migraine headache, the outcome used was pain initially moderate or severe becoming no worse than mild pain (no pain, mild pain) at 2 h. Single-dose ibuprofen 400 mg was better than aspirin and paracetamol.

Ketorolac and acetaminophen for orthopedic postoperative pain.

In a double-blind, single-dose, parallel-group study, ketorolac (5, 10, or 20 mg) was compared with acetaminophen (500 or 1000 mg) when taken by mouth for postoperative orthopedic pain. Analgesic measurements were made by trained nurse observers who used standard verbal rating and visual analog scales. Acetaminophen, 1000 mg, was statistically superior to 500 mg acetaminophen, demonstrating assay sensitivity. Ketorolac, 20 mg, was distinguished from 500 mg acetaminophen, 5 mg ketorolac, and 10 mg ketorolac, but not from 1000 mg acetaminophen. The higher doses of ketorolac induced a longer lasting peak analgesic effect than did acetaminophen, but the magnitude of the peak pain relief was changed little by an increased ketorolac dose. Overall, 10 mg ketorolac appeared equivalent to 1000 mg acetaminophen. Acetaminophen, 500 mg, induced less sedation than the higher doses of ketorolac, but neither drug caused untoward side effects.

Ibuprofen compared with ibuprofen plus caffeine after third molar surgery.

OBJECTIVES: To compare the relative merits of single doses of ibuprofen and ibuprofen plus caffeine in the treatment of pain after third molar removal. DESIGN: 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. SUBJECTS: 161 patients undergoing lower third molar removal. RESULTS: 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. CONCLUSIONS: 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.

Codeine 20 mg increases pain relief from ibuprofen 400 mg after third molar surgery. A repeat-dosing comparison of ibuprofen and an ibuprofen-codeine combination.

A combination of 20 mg codeine base and ibuprofen 400 mg was compared with ibuprofen 400 mg in a randomised double-blind cross-over study of multiple doses in 25 patients after 2-stage bilateral third molar removal. The combination produced significantly greater pain relief and doubled the hours of minimum pain intensity and maximal relief on the day of surgery. The patients rated the combination significantly better than ibuprofen alone, and the combination was preferred by 16 of the 22 patients expressing a preference. There was no significant increase in side-effect incidence with the combination. The 30% increase in analgesic effect may be of clinical benefit, and this trial design, cross-over with multiple dosing in out-patients, may be a sensitive test for analgesics, potentially more predictive of side-effect problems than single-dose studies.

Postoperative analgesia and vomiting, with special reference to day-case surgery: a systematic review.

BACKGROUND: Day-case surgery is of great value to patients and the health service. It enables many more patients to be treated properly, and faster than before. Newer, less invasive, operative techniques will allow many more procedures to be carried out. There are many elements to successful day-case surgery. Two key components are the effectiveness of the control of pain after the operation, and the effectiveness of measures to minimise postoperative nausea and vomiting. OBJECTIVES: To enable those caring for patients undergoing day-case surgery to make the best choices for their patients and the health service, this review sought the highest quality evidence on: (1) the effectiveness of the control of pain after an operation; (2) the effectiveness of measures to minimise postoperative nausea and vomiting. METHODS: Full details of the search strategy are presented in the report. RESULTS - ANALGESIA: The systematic reviews of the literature explored whether different interventions work and, if they do work, how well they work. A number of conclusions can be drawn. RESULTS-ANALGESIA, INEFFECTIVE INTERVENTIONS: There is good evidence that some interventions are ineffective. They include: (1) transcutaneous electrical nerve stimulation in acute postoperative pain; (2) the use of local injections of opioids at sites other than the knee joint; (3) the use of dihydrocodeine, 30 mg, in acute postoperative pain (it is no better than placebo). RESULTS-ANALGESIA, INTERVENTIONS OF DOUBTFUL VALUE: Some interventions may be effective but the size of the effect or the complication of undertaking them confers no measurable benefit over conventional methods. Such interventions include: (1) injecting morphine into the knee joint after surgery: there is a small analgesic benefit which may last for up to 24 hours but there is no clear evidence that the size of the benefit is of any clinical value; (2) manoeuvres to try and anticipate pain by using pre-emptive analgesia; these are no more effective than standard methods; (3) administering non-steroidal anti-inflammatory drugs (NSAIDs) by injection or per rectum in patients who can swallow; this appears to be no more effective than giving NSAIDs by mouth and, indeed, may do more harm than good; (4) administering codeine in single doses; this has poor analgesic efficacy. RESULTS-ANALGESIA, INTERVENTIONS OF PROVEN VALUE: These include a number of oral analgesics including (at standard doses): (1) dextropropoxyphene; (2) tramadol; (3) paracetamol; (4) ibuprofen; (5) diclofenac. Diclofenac and ibuprofen at standard doses give analgesia equivalent to that obtained with 10 mg of intramuscular morphine. Each will provide at least 50% pain relief from a single oral dose in patients with moderate or severe postoperative pain. Paracetamol and codeine combinations also appear to be highly effective, although there is little information on the standard doses used in the UK. The relative effectiveness of these analgesics is compared in an effectiveness 'ladder' which can inform prescribers making choices for individual patients, or planning day-case surgery. Dose-response relationships show that higher doses of ibuprofen may be particularly effective. Topical NSAIDs (applied to the skin) are effective in minor injuries and chronic pain but there is no obvious role for them in day-case surgery. RESULTS-POSTOPERATIVE NAUSEA AND VOMITING: The proportion of patients who may feel nauseated or vomit after surgery is very variable, despite similar operations and anaesthetic techniques. Systematic review can still lead to clear estimations of effectiveness of interventions. Whichever anti-emetic is used, the choice is often between prophylactic use (trying to prevent anyone vomiting) and treating those people who do feel nauseated or who may vomit. Systematic reviews of a number of different anti-emetics show clearly that none of the anti-emetics is sufficiently effective to be used for prophylaxis. (ABSTRACT TRUNCATE

Reporting of adverse effects in clinical trials should be improved: lessons from acute postoperative pain.

We assessed the quality of assessment and reporting of adverse effects in randomized, double-blind clinical trials of single-dose acetaminophen or ibuprofen compared with placebo in moderate to severe postoperative pain. Reports were identified by systematic searching of a number of bibliographic databases (e.g., MEDLINE). Information on adverse effect assessment, severity and reporting, patient withdrawals, and anesthetic used was extracted. Compliance with former guidelines for adverse effect reporting was noted. Fifty-two studies were included; two made no mention of adverse effects. No method of assessment was given in 19 studies. Twenty trials failed to report the type of anesthetic used, eight made no mention of patient withdrawals, and nine did not state the severity of reported adverse effects. Only two studies described the method of assessment of adverse effect severity. When all adverse effect data were pooled, significantly more adverse effects were reported with active treatment than with placebo. For individual adverse effects, there was no difference between active (acetaminophen 1000 mg or ibuprofen 400 mg) and placebo; the exception was significantly more somnolence/drowsiness with ibuprofen 400 mg. Ninety percent of trials reporting somnolence/drowsiness with ibuprofen 400 mg were in dental pain. All studies published after 1994 complied with former guidelines for adverse effect reporting. Different methods of assessing adverse effects produce different reported incidence: patient diaries yielded significantly more adverse effects than other forms of assessment. We recommend guidelines for reporting adverse effect information in clinical trials.

Single dose dipyrone for acute renal colic pain.

BACKGROUND: Renal colic pain is extremely painful and requires immediate treatment with strong analgesics. Dipyrone is the most popular non-opioid first line analgesic in many countries but in others it has been banned (e.g. USA, UK) because of its association with blood dyscrasias such as agranulocytosis. Since dipyrone is used in many countries (e.g. Brazil, Spain) there is a need to determine the benefits and harms of its use to treat renal colic pain. OBJECTIVES: To assess quantitatively the analgesic efficacy and adverse effects of single-dose dipyrone in adults with moderate to severe renal colic pain. SEARCH STRATEGY: Published reports were identified from electronic databases (MEDLINE, EMBASE, the Cochrane Library, LILACS) and additional studies were identified from the reference lists of retrieved reports. Date of the most recent search: January 2000. SELECTION CRITERIA: Inclusion criteria were: full journal publication; RCT with a double-blind design; adult patients with baseline renal colic pain of moderate or severe intensity; treatment arms which included dipyrone (oral, intramuscular or intravenous administration) and a control; single dose data. DATA COLLECTION AND ANALYSIS: Summed pain intensity and pain relief data were extracted and converted into dichotomous information to yield the number of patients with at least 50% pain relief over 15-30 minutes, 1-2 hours and six hours. The proportion of patients with at least 50% pain relief was calculated. Single dose adverse effect data were collected. MAIN RESULTS: Eleven studies with 1053 patients (550 on dipyrone) met the inclusion criteria. Unfortunately, few data were available for analysis; most analyses were based on the results of single, small trials and statistical pooling of the results was inappropriate. Efficacy estimates were calculated as the weighted mean percent of patients achieving at least 50% pain relief with the range of values from trials contributing to the analysis. However, these estimates were not robust. Commonly reported adverse effects with intravenous dipyrone were dry mouth and somnolence, and one study reported pain at the injection site. Insufficient information was available for safety analyses to be conducted. REVIEWER'S CONCLUSIONS: Limited available data indicated that single dose dipyrone was of similar efficacy to other analgesics used in renal colic pain, although intramuscular dipyrone was less effective than diclofenac 75 mg. Combining dipyrone with antispasmolytic agents did not appear to improve its efficacy. Intravenous dipyrone was more effective than intramuscular dipyrone. Dry mouth and somnolence were commonly reported with intravenous dipyrone. None of the studies reported agranulocytosis.

Relative efficacy of oral analgesics after third molar extraction.

OBJECTIVES: To compare the relative efficacy of analgesics after third molar extraction from systematic reviews of randomised, double blind studies. DATA SOURCES: Dental trials from systematic reviews of randomised, double-blind studies of analgesics in acute pain. DATA SELECTION: Number of patients with moderate or severe pain achieving at least half pain relief over 4 to 6 hours after a single oral dose of analgesic. DATA EXTRACTION: Independently by two reviewers. DATA SYNTHESIS: Use of dichotomous information from active and placebo treatments, first to calculate the statistical significance using relative risk, and then to evaluate the clinical relevance using number needed to treat (NNT). Non-steroidal anti-inflammatory drugs (NSAIDs) and cyclo-oxygenase-2 (COX-2) inhibitors had the lowest (best) NNTs for the outcome of at least half pain relief over 4-6 hours compared with placebo. With the best performing analgesics, 50-70 patients out of 100 had good pain relief compared with about 10 out of 100 with placebo. Only paracetamol 600/650 mg plus codeine 60 mg was associated with any significant increase in any patient experiencing an adverse event. CONCLUSIONS: NSAIDs and COX-2 inhibitors have the lowest (best) NNTs. They may also have fewer adverse effects after third molar surgery, though conclusive evidence is lacking. At least 80% of analgesic prescribing by UK dentists is in line with the best available evidence on efficacy and safety.

A conservative method of testing whether combination analgesics produce additive or synergistic effects using evidence from acute pain and migraine.

Fixed-dose combination analgesics are used widely, and available both on prescription and over-the-counter. Combination drugs should provide more analgesia than with any single drug in the combination, but there is no evidence in humans about whether oral combinations have just additive effects, or are synergistic or even subadditive. We suggest that the measured result for the combination would be the summation of the absolute benefit increase (effect of active drug minus effect of placebo) of each component of a combination if effects were (merely) additive, and greater than the sum of the absolute benefits if they were synergistic. We tested measured effects of combination analgesics against the sum of the absolute benefits in acute pain and migraine using meta-analysis where individual components and combinations were tested against placebo in the same trials, and verified the result with meta-analyses where individual components and combinations were tested against placebo in different trials. Results showed that expected numbers needed to treat (NNT) for additive effects were generally within the 95% confidence interval of measured NNTs. This was true for combinations of paracetamol plus ibuprofen and paracetamol plus opioids in acute pain, and naproxen plus sumatriptan in migraine, but not where efficacy was very low or very high, nor combinations of paracetamol plus dextropropoxyphene. There was no evidence of synergy, defined as supra-additive effects.

Relative efficacy of oral analgesics after third molar extraction--a 2011 update.

This article provides a summary of the efficacy, and relative efficacy, of 38 different drugs or drug combinations tested in standard postoperative pain trials. It will help clinicians and patients make informed choices about analgesia based on pain relief, duration of action, and adverse events, which can then be put into context for the individual patient, depending on local availability. This article highlights the fact that no single drug is effective in all patients--even the best drugs fail to provide good levels of pain relief in at least 30%. These patients should try a different analgesic.

A multiple dose comparison of combinations of ibuprofen and codeine and paracetamol, codeine and caffeine after third molar surgery.

In a randomised, double-blind, double-dummy, multiple dose, crossover study in 30 patients we compared an ibuprofen/codeine combination (400 mg ibuprofen/25.6 mg codeine phosphate) with a paracetamol/codeine/caffeine combination (1 g paracetamol/16 mg codeine phosphate/60 mg caffeine) for pain relief over 6 days after two-stage bilateral lower third molar removal. The ibuprofen combination produced significantly greater analgesia than the paracetamol combination, both on single-dose analysis of the first and second days and on multiple-dose measures for days 1, 2, 3 and 4. The mean incidence of adverse effects over the 6 days was 20% for both combinations. This trial design (crossover with multiple dosing in outpatients) is a sensitive way of testing for analgesia, and is potentially more predictive of adverse effect problems than single-dose studies. It confirms that multiple dosing may show increased efficacy.

Comparison of flupirtine maleate and dihydrocodeine in patients following surgery.

Flupirtine maleate 100 mg was compared with dihydrocodeine 60 mg when given by mouth to 50 women on the first 3 days following abdominal hysterectomy in a double-blind parallel-group trial. The analgesia produced was similar for both preparations, and the consumption of active drug was the same in both groups. The only significant differences in side-effects were an increased frequency of depression in patients receiving flupirtine and of sleepiness in those receiving dihydrocodeine.