6. Analgesic clinical efficacy and safety in dental pain management

Evidence-based medicine strongly supports the evaluation of analgesic efficacy and safety. The majority of this research uses the third-molar extraction model of acute dental pain to determine relief of pain intensity over time with different available analgesics. The clinical efficacy of dental analgesics is focused on comparison of individual analgesics and placebo and monotherapy analgesics with combined therapy.

Efficacy and safety of analgesic drugs is shown to be enhanced through the use in combination due to the reduction of single drug component. Usually, the choice of analgesic is based on personal preference. In systematic reviews for dental and general surgical randomized controlled trials with naproxen, diclofenac and rofecoxib, they were shown to be superior compared to placebo and also COX-2 inhibitors demonstrated equipotent efficacy relative to NSAIDs.

Moreover in dental and orthopedic pain, valdecoxib, celecoxib, ibuprofen and acetaminophen alone or with oxycodone demonstrated superiority of COX-2 inhibitors compared to acetaminophen, but not to ibuprofen alone. Also, oral ibuprofen is significantly superior to placebo and when the doses were maximal the effect were enhanced.

When compared to diclofenac, ibuprofen was less efficacious even after showing a reduction by at least 50% of pain for 100% of patients participated. Acetaminophen was also proven to be similarly efficacious in general and orthopedic surgery and less effective in dental surgery compared to NSAIDs. When it is combined with opioids such as codeine or oxycodone, it was shown to be superior compared to placebo; however, it was more prone to side effect. The same was proven with tramadol alone.

In general, NSAIDs demonstrate higher efficacy in dental pain and are considered as the main alternative and drug of choice for dental pain. However, even though opioids are relatively less effective, they may be considered when NSAIDs are contraindicated and also different combination could be administered for some patients that require adequate pain relief [82].

Common reported adverse events of NSAIDs are dyspepsia, gastric ulceration-bleeding, diarrhea from COX-1 inhibitors, cardiovascular disease (congestive heart failure, atherothrombosis, myocardial infarction, ischemic stroke), reduced renal perfusion, or nephrotic syndrome accompanied with edema, acute kidney failure in rare cases from COX-2 inhibitors. Ibuprofen use in normal doses is one of the drugs with least risk or alternative option as selective COX-2 inhibitors. Acetaminophen adverse effects resulting from their higher dosage, chronic use, or in patient with liver disease includes liver toxicity, prolongation of prothrombine time, urticaria or skin rashes and acute renal tubular necrosis. Severe hepatotoxicity was reported in patients with risk factors such as HIV, hepatitis C and chronic alcohol users. In postoperative pain, a single dose usage and rational prescribing is demonstrated to be safe.

Moreover, narcotic analgesics have more frequent adverse effects and many patients abandoned treatment which make them poor choice in dental pain. When contemplating surgery, it is recommended to suppress NSAID medication from 1–2 to 4–5 days, which also depends on the drug type and dose regimen. Analgesic combination, which contains NSAIDs, is recommended to be used with caution only in short course for the acute dental pain [41, 83– 86]. These above-mentioned side effects usually tend not to occur with the occasional use of NSAIDs, which makes these drugs safe in dental practice. NSAID usage for more than 10 days should be consulted with the practitioner. Even though they are considered relatively safe within the recommended dosage for use of up to 10 days, cautions should be exercised in NSAIDs-exacerbated respiratory disease, asthma, patients with prior myocardial infarction who are receiving antithrombotic therapy and those with a history of renal disease [87, 88].

Strategies to lower risk events for gastrointestinal toxicity from NSAIDs include the use of the lowest dose, switch to acetaminophen or COX-2 inhibitors, or antiulcer cotherapy use (PPI, H2-blockers, antacids, prostaglandins). Cardiovascular-related adverse effects have resulted in rofecoxib and valdecoxib being withdrawn from the market. However, uses were for a long period of time and dose dependent or even in short course of treatments for 10 days after bypass surgery. Currently, celecoxib, etoricoxib, lumiraxocib and parecoxib, with better cardiovascular risk profiles, are still in the market. Hence, NSAIDs may increase the risk for myocardial infarction, in particular those with more COX-2 selectivity such as diclofenac. Taking this into consideration, avoiding COX-2 inhibitors and following treatment with antiulcer drugs is recommended in high risk patients [82]. Ibuprofen and naproxen are considered the safest NSAIDs. Overall risk from analgesic used in dentistry is low and importantly when they are used in acute dental pain. Moreover, the most serious safety concerns about the use of opioids are the side effect profile which includes respiratory depression, dependence, sedation, euphoria, constipation, cognitive dysfunction, pruritus, nausea and immunologic and endocrine effects, which are more prone from μ receptor activity. Dependence is another challenge and this occurs more in severe acute, chronic and terminal pain for longer than a week and after repeated administration. Furthermore, tolerance to opioids is developed when higher doses are used.

Selective κ agonist such as nalbuphine is shown to be safer even though this should never be given to a patient who is dependent. Important care is recommended for codeine metabolism from CYP2D6 ultrarapid metabolizers, which are more prone to morphine-induced side effects or for CYP2D6 deficient or patient who are on inhibitors of this cytochrome may not produce analgesic effect of hydrocodone and oxycodone. Methadone has potential to cause cardiac arrhythmia. Due to this pretreatment and periodic cardiograms are recommended for patients suspected for drug interactions or increasing methadone dosing. Important care should also be taken with conversion of one opioid to another from opioid conversion tables (for example, morphine to methadone). Regarding treatment of withdrawal, partial agonists such as buprenorphine is recommended [19, 89].

In general, NSAIDs demonstrate higher efficacy in dental pain and are considered as the main alternative and drug of choice for dental pain. However, even though opioids are relatively less effective, they may be considered when NSAIDs are contraindicated and also different combination could be administered for some patients that require adequate pain relief [82].

Common reported adverse events of NSAIDs are dyspepsia, gastric ulceration-bleeding, diarrhea from COX-1 inhibitors, cardiovascular disease (congestive heart failure, atherothrombosis, myocardial infarction, ischemic stroke), reduced renal perfusion, or nephrotic syndrome accompanied with edema, acute kidney failure in rare cases from COX-2 inhibitors. Ibuprofen use in normal doses is one of the drugs with least risk or alternative option as selective COX-2 inhibitors. Acetaminophen adverse effects resulting from their higher dosage, chronic use, or in patient with liver disease includes liver toxicity, prolongation of prothrombine time, urticaria or skin rashes and acute renal tubular necrosis. Severe hepatotoxicity was reported in patients with risk factors such as HIV, hepatitis C and chronic alcohol users. In postoperative pain, a single

Moreover, narcotic analgesics have more frequent adverse effects and many patients abandoned treatment which make them poor choice in dental pain. When contemplating surgery, it is recommended to suppress NSAID medication from 1–2 to 4–5 days, which also depends on the drug type and dose regimen. Analgesic combination, which contains NSAIDs, is recommended to be used with caution only in short course for the acute dental pain [41, 83– 86]. These above-mentioned side effects usually tend not to occur with the occasional use of NSAIDs, which makes these drugs safe in dental practice. NSAID usage for more than 10 days should be consulted with the practitioner. Even though they are considered relatively safe within the recommended dosage for use of up to 10 days, cautions should be exercised in NSAIDs-exacerbated respiratory disease, asthma, patients with prior myocardial infarction who are receiving antithrombotic therapy and those with a history of renal disease [87, 88].

Strategies to lower risk events for gastrointestinal toxicity from NSAIDs include the use of the lowest dose, switch to acetaminophen or COX-2 inhibitors, or antiulcer cotherapy use (PPI, H2-blockers, antacids, prostaglandins). Cardiovascular-related adverse effects have resulted in rofecoxib and valdecoxib being withdrawn from the market. However, uses were for a long period of time and dose dependent or even in short course of treatments for 10 days after bypass surgery. Currently, celecoxib, etoricoxib, lumiraxocib and parecoxib, with better cardiovascular risk profiles, are still in the market. Hence, NSAIDs may increase the risk for myocardial infarction, in particular those with more COX-2 selectivity such as diclofenac. Taking this into consideration, avoiding COX-2 inhibitors and following treatment with antiulcer drugs is recommended in high risk patients [82]. Ibuprofen and naproxen are considered the safest NSAIDs. Overall risk from analgesic used in dentistry is low and importantly when they are used in acute dental pain. Moreover, the most serious safety concerns about the use of opioids are the side effect profile which includes respiratory depression, dependence, sedation, euphoria, constipation, cognitive dysfunction, pruritus, nausea and immunologic and endocrine effects, which are more prone from μ receptor activity. Dependence is another challenge and this occurs more in severe acute, chronic and terminal pain for longer than a week and after repeated administration. Furthermore, tolerance to opioids is developed when

dose usage and rational prescribing is demonstrated to be safe.

126 Pain Relief - From Analgesics to Alternative Therapies

higher doses are used.

Recently, there have been important developments in the investigation of lower addictive potential opioids such as tamper-resistant extended release, also opioid abuse screening tools, genetic testing and fMRIs for patients at risk of opioid abuse while maintaining treatments for patients with appropriate management.

Even though recent research has shown that a number of potential predictors for personalization of therapy exist, there is still insufficient evidence for opioid prescribing from patient's characteristics. Data-based personalized prescribing of opioids for optimization of analgesic effectiveness and mitigate risks of opioid-related mortality and abuse is highly desirable with the potential to benefit patients by raising world clinical care and optimizing cost effectiveness of opioid analgesic therapy [90].
