8. Significant drug interactions of analgesics

NSAIDs display major interactions when used alongside anticoagulant and antiplatelet effects of warfarin and clopidrogel, which results in enhancement of their effects and increased risk of bleeding. In this situation acetaminophen is an appropriate choice at the lowest possible dose, in short-term treatment only. Ibuprofen use in patients taking cardioprotective aspirin does not interfere with its antiplatelet activity, even though there are studies that demonstrate reduced cardioprotective benefits and increase gastrointestinal risk, in contrast to diclofenac or acetaminophen which did not influence effects of aspirin on platelet function [86]. Moreover, patients taking daily aspirin for cardiovascular disease prevention should avoid chronic use of ibuprofen and FDA recommends taking ibuprofen in intervals of more than 8 h before or more than 30 min after the immediate release of aspirin to reduce potential interaction in platelet function [40]. Concurrent use of NSAIDs with warfarin or corticosteroid may increase gastrointestinal risk. They also increase the risk of gastrointestinal ulceration in concomitant use with biphosphonates. Effects of antidiabetic sulfonylureas are increased with coadministration of NSAIDs.

A decrease of renal extraction of methotrexate is shown with the use of NSAIDs, which can bring to its toxicity. Also, the serum concentrations of lithium are raised and non-NSAID analgesic should be recommended. Additionally, fluconazole was shown to increase celecoxib concentration due to its metabolism inhibition.

Interactions with lesser significance are NSAIDs use with ACE inhibitors, diuretics, Ca-channel bBlockers and beta-blockers which results in diminished antihypertensive effects. However, short-term use does not pose a major risk in healthy individuals, but in hypertensive patients and especially in the elderly if the treatment will be continued for a long term a careful selection and close monitoring is required. Antacids were shown to decrease NSAIDs effects. NSAIDs are also found to interact with SSRIs (selective serotonin reuptake inhibitors) to increase the risk of bleeding including also upper gastrointestinal and postoperative bleeding [37, 105, 106]. Acetaminophen has very few drug interactions. Carbamazepine as metabolic inducer may decrease drug levels of acetaminophen. Its combination with alcohol or drugs that harm the liver may increase the risk for liver toxicity.

Dental practitioners should be aware of these interactions and use analgesic drug therapy within the limit of dosage or interval of use and in carefully considered combinations. Furthermore, they should avoid them when there is increased risk for toxicity [81, 107]. Narcotic analgesic interactions include antipsychotics (phenotiazines) which enhance their hypotensive effect and also CYP2D6 inhibitors (cimetidine, chlorpheniramine, fluoxetine and quinidine), which inhibit their effects including hydrocodone. Inhibitors or inducers of CYP3A4 cause clinical significant interactions when used with morphine, oxycodone and methadone by mediating opioid toxicity or impairment of pain treatment. Also, SSRIs and MAOIs effects are more associated with meperidine, methadone, tramadol, buprenorphine, oxycodone, hydrocodone, pentazocine and fentanyl, which may also result in the cause of the serotonin syndrome. Barbiturates may enhance their sedative effects. Also an increase of meperidine metabolism is induced by phenytoine. Taking this into consideration physicians should recognize and monitor patients carefully for drug interactions and possibly try to avoid polypharmacy [89, 108, 109].
