Comment on controlling dental post-operative pain and the intraoral local delivery of drugs

Abstract

The results of numerous double-blind, placebo-controlled clinical trials consistently demonstrate that nonsteroidal antiinflammatory drugs should be the first line agents in treating postsurgical dental pain. Additive and potential opioid-sparing effects have also been reported in oral surgery pain by combining an optimal dose of an NSAID with acetaminophen 500 mg. While opioid combination drugs are indicated in some dental postsurgical patients, clinicians can no longer ignore the scourge of prescription opioid abuse in the United States. Other potential opioid sparing strategies include the use of locally delivered antimicrobial/antiinflammatory agents such as Bexident Post or extended duration local anesthetic agents such as liposomal bupivacaine placed directly in or in the vicinity of the extraction socket.

Keywords: :

• Ibuprofen
• Liposomal bupivacaine
• Local delivery of drugs
• NSAIDs
• Post-surgical dental pain
• Prescription opioid abuse

In this issue of CMRO, Dr Lope-Lopez and colleagues1 demonstrate how a topical oral gel that contains an approved antiseptic, a vitamin derivative, a plant derivative and a derivative of the exoskeletons of crustaceans (Bexident Post or BP) applied directly into a tooth extraction socket appears to reduce postoperative pain, inflammation and improve healing compared to a bicarbonate oral rinse (BC). It should be emphasized that these improved outcomes were obtained while patients in both treatment groups were taking around the clock ibuprofen 600 mg. Based on previous research and clinical experience we were a bit surprised concerning the relatively high number of rescue analgesic pills that were taken in both treatment groups (albeit less in the BP group). The genesis of postsurgical dental pain and inflammation is dependent on the synthesis of prostaglandins from its arachidonic acid precursor2. Ibuprofen and other NSAIDs possess a favorable benefit versus risk profile in the short-term treatment (one week or less) of these dental patients, who are typically young healthy adults without cardiovascular disease3^,4. We have previously recommended around the clock ibuprofen at a 400–600 mg dosage strength (or an equivalent dose of another NSAID) as first line treatment for moderately severe postsurgical dental pain5^,6. It may surprise some clinicians to find that single-entity opioid analgesics, including 60 mg of immediate-release morphine or up to 100 mg of tapentadol, are inferior to ibuprofen 400 mg in treating the pain following the surgical removal of impacted third molars7. Another strategy that has proven effective in reducing opioid exposure in more severe postsurgical dental pain is to combine an optimal dose of an NSAID with acetaminophen 500 mg. This provides an additive analgesic effect and reduces the number needed to treat (NNT) compared to an NSAID alone6. Acetaminophen doses should be limited to no more than 3000 mg per day.

As demonstrated in the Lope-Lopez et al. study report, intraoral surgery and dental diseases provide an opportunity to apply therapeutic agents directly to the site of the oral diseases or surgical trauma. Local delivery of drugs has several advantages to systemically administered agents. The dose or formulation concentration provided to the site can be much higher because the therapeutic agent need not be distributed throughout the body before reaching the oral site of action. The higher dose at the site of action can improve the efficacy of many marginally effective therapeutic agents. Consequently, much of the potential for systemic side effects can also be avoided. The use of local delivery therapeutics does require some mechanism to maintain the agent within the oral environment for an adequate period of time to allow action of the medication. As demonstrated by the BP formulation, this can be accomplished by using therapeutic agents that have substantivity (such as chlorhexidine) that adhere to oral mucosa. Other strategies to improve the sustained release and efficacy of locally delivered oral therapeutic agents include fluoride varnishes and locally delivered antibiotics into periodontal pockets (tetracycline, minocycline)8.

Similar to the BP formulation that was placed directly into the extraction socket following the completion of surgery, another potential strategy for enhanced pain control with an opioid-sparing effect is to place the liposomal formulation of bupivacaine, marketed as Exparel^†, directly into the socket or employ liposomal bupivacaine infiltration injections around the extraction socket9. The administration of liposomal bupivacaine has not been formally studied or at least reported in a peer-reviewed journal and should be evaluated for both pain control and healing at the extraction site. While this novel formulation of bupivacaine has a reported duration of action of 48–72 hours with a significant opioid-sparing effect in various postsurgical pain models10–12, there could be an analgesic lag of four to five hours. The drug is currently not approved to provide regional local anesthesia. Therefore when performing impacted third molar cases, intraoperative regional local anesthesia would have to be provided by the conventional formulation of 0.5% bupivacaine plus 1:200,000 epinephrine which possesses a duration of soft tissue and periosteal anesthesia for 6–9 hours13, rather than employing a shorter-acting local anesthetic such as 2% lidocaine plus 1:100,000 epinephrine, since pain could break through with the latter before sufficient bupivacaine was released from the liposomes.

The use of non-opioid analgesics and the effective local delivery of analgesics and anti-inflammatory agents provides a means of avoiding systemic opioid agents and the scourge of prescription opioid abuse now rampant in the United States and other countries14–16. Opioids and opioid combination drugs may be indicated in many postsurgical pain patients based on medical history, potential drug interactions, or insufficient pain relief with NSAIDs or NSAID/acetaminophen combinations17–20. However, when one writes a ‘typical prescription’ for twenty tablets of acetaminophen 300 mg plus hydrocodone 5 mg (Vicodin)14 and the patient only uses eight or nine of these pills, there is always the chance that these extra pills will be removed from the medicine cabinet by someone other than the patient and either diverted or used for ‘recreational purposes’. While we certainly do not want to promote ‘opioid phobia’, this growing problem can no longer be ignored by clinicians. Employing drugs with opioid-sparing effects for acute pain such as NSAIDs, acetaminophen and liposomal bupivacaine will hopefully have some positive impact on this problem.

Transparency

Declaration of funding

This editorial was not funded.

Declaration of financial/other relationships

E.V.H. is a professor of oral surgery and pharmacology. He has disclosed that he has received grant funding from Pfizer Consumer Health Care, the maker of various ibuprofen containing products, and AAI Pharmaceuticals, the former manufacturer of liquid filled diclofenac soft gelatin capsules. He has also disclosed that he has served as a consultant for McNeil Pharmaceuticals, the maker of acetaminophen and ibuprofen products. P.A.M. is a professor of pharmacology and dental public health. He has disclosed that he has served as medical director and/or a research consultant to several pharmaceutical companies manufacturing and marketing local anesthetic products including Dentsply Pharmaceutical Division, Kodak Dental Systems, Septodont USA, St Renatus, Novalar, and Novocol of Canada Inc.

Notes

*Bexident Post is a registered trade name of Isdin Barcelona, Spain.

^†Exparel is a registered trade name of Pacira Pharmaceuticals, Inc., Parsippany, NJ.

^‡Vicodin is a registered trade name of AbbVie Inc., North Chicago, IL.