* Weak agonist/norepinephrine and serotonin reuptake inhibitor; variable response and threshold for nausea and vomiting; tolerability may be improved by starting with 25 mg/day and slowly titrating to usual dose over a few weeks; 50 mg equivalent to codeine 60 mg; 100 mg comparable to aspirin 650 mg plus codeine 60 mg; maximum dose 400 mg/d for IR and 300 mg/d for ER; also available in a fixed-dose combination with acetaminophen (Ultracet, others). Note . Adapted from: “Tramadol: what have we learned in the last 25 years? by M. Donaldson & J.H. Goodchild, 2021, General Dentistry, 69(4), 14-18.; “Nonopioid analgesics,” by E. V. Hersch and R. Dionne, 2016, in F. J. Dowd, B. Johnson, and A. Marriotti, (Eds.), Pharmacology and Therapeutics for Dentistry (7th ed.; pp. 257-275), St. Louis, MO: Mosby; and “Treatment Guidelines From The Medical Letter: Opioids for Pain,” 2018, The Medical Letter, 60 (1544), 57-64. New, novel analgesics
In 1989, ketorolac became an approved NSAID for injectable use as an analgesic. Over the last two decades, many studies have been conducted involving ketorolac, some looking specifically at various routes of administration (Vadivelu et al., 2015). SPRIX® is an intranasal formulation of ketorolac indicated in adult patients for the short term (up to 5 days) management of moderate to moderately severe pain that requires analgesia at the opioid level. At the time of its launch, there was significant interest in this product throughout the dental community since this seemed to offer a more targeted delivery of a NSAID for patients suffering orofacial pain. Unfortunately, clinical trials have not shown any level of superior efficacy over traditional oral medications and the cost differential between the intranasal and oral formulations often makes this new medication prohibitive for many patients (Stentz et al., 2018; Lexicomp, 2021). More recently there has been an increased interest in a new product utilizing liposomal bupivacaine (Exparel®) as a possible therapy to help reduce reliance on prescribing opioids for post-operative pain management given the very long and sustained effect of this formulation (up to 96 hours) compared to standard bupivacaine and other traditional local anesthetics Not so new, novel analgesics While dexamethasone has been available in the United States since 1958 under the brand name Decadron®, the first recorded use of dexamethasone for an endodontic procedure was not until 1968 (Estefan-Estefan, 1968). Since then, the oral formulation has been useful for post-operative analgesia, and is more commonly recognized as a 6-, 10- or 13-day tapered regimen (Dexpak®). These tapered regimens are not required to prevent adrenal insufficiency, since it typically takes fourteen days of supraphysiological doses of exogenous glucocorticoids to suppress the hypopituitary axis and a simpler strategy would be to consider dexamethasone 4-8mg orally twice a day for up to 48 hours after dental surgery as demonstrated in a recent systematic review on this subject (Varvara et al., 2017).
(Lexicomp, 2018). OHCPs are already adept at the use of local anesthetics, so the administration of a very long-acting local anesthetic around the time of dental procedures which could potentially lessen or eliminate the need for any post-operative analgesic, especially opioids, may seem like a perfect solution. Unfortunately, there are some significant patient safety issues associated with the liposomal formulation of bupivacaine beyond the exorbitant cost (over $200 per injection), compared to commercially available bupivacaine in dental cartridges. The most recent published systematic review and meta-analysis on this subject concurs that, “The overall evidence level was low [for the safety of local liposomal bupivacaine infiltration], which means that further research is likely to significantly alter confidence levels in the effect, as well as potentially changing the estimated value” (Zhang, Yang, & Zhang, 2017). A Cochrane review published later that same year had very similar conclusions (Hamilton et al., 2017). The following year Goodchild and Donaldson answered the question, “Does liposomal bupivacaine fulfill an unmet need in dentistry?” with an emphatic “no” based on current evidence (Goodchild & Donaldson, 2018b). Alternatively, dexamethasone has also been successful as an intramuscular injection postoperatively for the control of pain, trismus, and swelling following third molar extractions as shown in a recent systematic review and meta-analysis (Fernandes et al., 2019). In fact, Chen et al., found that a single submucosal intraoperative injection of dexamethasone up to 10mg reduced not only early and late edema, but also pain and early trismus after third molar surgery (Chen, Chen, Hu, Feng, & Song, 2017). This new data on an old drug may alter the mnemonic for our perfect prescription in Figure 3 from “2-4-24,” to, “1-2-4-24” where the “1” would represent a single intraoperative dose of dexamethasone up to 10mg (Donaldson & Goodchild, 2019b).
PHARMACOTHERAPY FOR NEUROPATHIC OROFACIAL PAIN
Nociceptive pain can play a role in the initiation and maintenance of persistent neuropathic orofacial pain, and treatment may require analgesics (for nociceptive pain), alone or in combination with medications for neuropathic pain. Neuropathic pain is defined by Treede and colleagues as, “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system” (Treede et al., 2008). Unlike nociceptive pain, neuropathic pain does not reflect actual tissue damage, but can be triggered by tissue injury and usually persists long after the injury has healed (Jay & Barkin, 2014). Based on clinical examinations of individuals with neuropathic pain, researchers have developed several survey questionnaires to help differentiate individuals experiencing neuropathic pain from those experiencing other pain conditions. These diagnostic tools include the Neuropathic Pain Questionnaire (NPQ) and the Self-Administered Leeds Assessment of Neuropathic Symptoms and Signs (S- LANSS; Bennett, Smith, Torrance, & Potter, 2005; Krause & Backonja, 2003).
Neuropathic orofacial pain includes the classic cranial neuralgias (e.g., trigeminal and glossopharyngeal) and postherpetic neuralgia. Other forms of neuropathic orofacial pain include primary stomatodynia (burning mouth), phantom tooth pain (atypical odontalgia), and traumatic nerve injuries. The hallmark signs of neuropathic pain are mechanical hyperalgesia (extreme sensitivity to pain secondary to touch) and allodynia (pain due to a stimulus that does not normally provoke pain), constant burning or paroxysmal shooting pain, and, less commonly, constant aching or pressure pain (Rotpenpian, & Yakkaphan, 2021). A minority of patients may not have pain as the primary manifestation of neuropathy but instead experience dysmorphic symptoms, paresthesia, and/or altered taste. Primary neuropathic pain may also have an inflammatory component, and effective management may require medications from multiple classes (e.g., anti-inflammatory medications, antibiotics). Figure 4 illustrates a general approach to management of the major orofacial neuropathic pain conditions and updates the algorithm proposed by Finnerup and colleagues in 2005 (Finnerup, Otto, McQuay, Jensen, & Sindrup, 2005; Chan, et al., 2021).
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