February 1, 2015
by Dr. Alia El-Mowafy &Dr. Peter Nkansah
It has been estimated that seventy-five percent of adults experience an element of dental anxiety, and that in ten percent of patients, such fear can prevent them from making a visit to the dental office in the early phase of their symptoms.1 These patients quite often delay treatment until their disease process has progressed significantly and their pain is severe. The management of this pain and its underlying cause often necessitates invasive procedures. Whether it be oral surgery, endodontic treatment or periodontal surgery, there is inevitably a higher risk involved in these more complex interventions. The unavoidable tissue trauma in these procedures only exacerbates their pain and further increases their anxiety both peri- and post-operatively. An experience such as this may be traumatic to an already anxious patient and potentially increase their dental phobia. Effective pain management in these patients is essential to ensure patient compliance and to help in alleviating their fear and anxiety. Not only it is important to manage post-operative pain from this clinical perspective, but it is essential in maintaining a positive, trusting patient-clinician relationship. One of the very effective skillsets that a dentist can present is the ability to alleviate a patient’s anxiety by effectively controlling pain.
Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential damage.1 After initial peripheral detection by nociceptors, the perception of nociception occurs in the brain. Dental pain is of a musculoskeletal origin, and it is typically comprised of both inflammatory and acute pain. Whereas acute pain due to tissue insult is processed by the fast A-delta fibres, inflammatory pain is chemically mediated by stimulating the slow C-Fibres.2 It has been reported that inflammatory pain reaches its peak 48-72 hours post-surgery.3 This pain response occurs from the release and subsequent synthesis of several biochemical mediators in response to tissue injury. Following any tissue trauma, such as oral surgery, the cardinal signs of inflammation: pain, swelling redness and heat will present. The response is produced by a cascade of events which ultimately lead to the production of prostaglandins, leukotrienes and thromboxanes, the key players in inflammation and homeostasis.4 Phospholipids initiate the synthesis of these chemical mediators by triggering two enzymatic pathways: the lipoxygenase pathway and the cyclooxygenase pathway. The lipoxygenase pathway produces leukotrienes. The cyclooxygenase pathway is further split in two pathways mediated by the cyclooxygenase-1 enzyme (COX-1) and the cyclooxygenase-2 enzyme (COX-2) which produce prostaglandins. Prostaglandin receptors are found in the blood vessels, GI tract, brain and kidney where they play key roles in homeostasis, digestion, renal function, blood pressure and temperature regulation. Furthermore COX-1 also produces thromboxane-A2 which plays a key role in platelet aggregation. COX-2 produces the prostaglandins that are primarily responsible for inflammation and pain. Effective pain management must take this series of events into consideration when choosing medication to prevent and alleviate post-operative pain.3 Many medications work to depress this nociceptive response either peripherally or centrally.
While pharmacological options often seem complex and sometimes overwhelming, we can simplify the process by classifying drug options into two broad categories: non-opioids and opioids. This article aims to discuss an approach to pain management with non-opioid pharmacological options. The World Health Organization introduced the analgesic ladder in 1986 as an approach to the management of cancer pain.5 It has been further extrapolated as an approach to pain management in various conditions across many fields of medicine. Clinicians are advised to manage pain with the suggested management at the bottom of the ladder, proceeding up the ladder only when the pain persists or increases. This approach is based upon a few simple recommendations that are relevant to the management of any acute or chronic pain.5 Medications should be given at regular intervals and not as needed. The duration of action of the medication indicates how often it should be administered in order to maintain a therapeutic level. A consecutive dose should be administered prior to the end of duration of the previous dose in order to inhibit the synthesis of the chemical mediators of pain. These intervals should then also be catered to the patient’s need.5 Pain is an individual experience, and it is crucial to treat pain on an individual basis and not according to one’s own perception of the level of pain expected with a given procedure. The choice of analgesics should be made according to both the type and intensity of pain that the patient is experiencing, which should be evaluated on a pain intensity scale, once again reinforcing the need for individualized management plans. The final recommendation, which may be the most important, is attention to detail and explanation.5 In order for the analgesic management to be effective, it must be carried out by the patient according to your prescribed plan. To ensure adequate relief, this plan should be discussed with the patient in detail so that they understand exactly how and when they are to take their medications before they leave the dental office.
Acetaminophen has a weaker anti-inflammatory effect than non-steroidal anti-inflammatory drugs (NSAIDs), however it is generally better tolerated. Despite its weaker effect, it is still capable of providing effective analgesia for mild pain, while exhibiting fewer side effects than NSAIDs. Its mechanism of action was not well understood in the past; there is now research that shows acetaminophen has not only peripheral but central activity as well. The central activity is believed to be related to endocannabinoids that modify various physiological processes including pain.6 Although acetaminophen does not have direct activity on endocannabinoids, one of its metabolites shows cannabinoid-like activity. This is at least similar to the use of medicinal marijuana in the management of cancer pain where the analgesic properties arise from its action on the endocannabinoid system. It has become generally accepted that acetaminophen’s peripheral action is on COX-1 and COX-2 enzymes by inhibiting the formation of a component that is essential for these enzymes’ activity.7 However, when there are substantial levels of the COX precursor arachidonic acid, it has minimal effects. This results in its weaker anti-inflammatory properties making it ineffective in treating diseases that are inflammatory in nature, such as rheumatoid arthritis. It has, however, been adequate in treating both the pain and inflammation in certain patients following oral surgery. In a trial published by Bjornsson et al (2003), 4 g daily of acetaminophen produced similar anti-inflammatory effects to 2400 mg of ibuprofen locally following oral surgery.8 Its apparent COX-2 selectivity gives it favourable gastric tolerance and poor anti-platelet activity. Acetaminophen has come under fire due to the increasing rate of liver failure resulting from intentional and unintentional overdose. It is currently the most common cause of acute liver failure in the United States. The risk of hepatotoxicity increases in people who are alcoholics, fasting or malnourished, as a lower dose is required to reach t
oxic serum levels.7 This finding reiterates the fact that attention to detail is prudent when both prescribing and instructing the patient about the use of acetaminophen. It is essential to ensure that your patient is not already taking an acetaminophen blend such as opioid or antitussive combinations and to ensure that they fully understand their medication dosage and frequency.7 The therapeutic doses are 500 mg, 650 mg, or 1000 mg every four to six hours ensuring to not exceed 4000 mg in a 24 hour period.3
NSAIDs are analgesic, antipyretic, and anti-inflammatory in action. They achieve this effect by reversibly inhibiting the COX-1 and COX-2 enzymes. This mechanism understandably provides the source of its associated side effects. At low doses, the analgesic and anti-pyretic effects are the dominant mechanism of pain relief, with the anti-inflammatory action playing a smaller role. However as the dose increases, these drugs exhibit a “ceiling” effect in their analgesic properties.9 A further increase in analgesia will not be observed with a further increase in the dose past this point. In order to express their anti-inflammation effects, NSAIDs should be administered on the higher end of their therapeutic range.9 Within the typical suggested dosing range, analgesic requirements fall within the low range whereas inflammation falls on the high end. That being said, inflammation caused by dental treatment is typically managed sufficiently with doses on the lower end of the range. The prototypical drug for this category of non-opioid is ibuprofen. Overall, ibuprofen was found to be most beneficial when administered as an 800 mg dose every six to eight hours; with 400-600mg doses every four to six hours providing an alternative option for adequate analgesia in many patients.3 Its daily maximum dose is 2400 mg. The effectiveness of either option is variable on an individual basis, once again reinforcing the need for open communication and clear instruction between clinician and patient. Preoperative administration of NSAIDs has also been shown to be effective in reducing post-operative pain and swelling. Because the mechanism of action of these drugs is to block production of chemical pain mediators they will have little effect on those already produced.9 For this reason they are most efficacious when given pre-operatively to prevent initiation of the inflammatory response. The same ideology would also apply to the timing of administration in relation to local anesthetic effects, specifically administering NSAIDs prior to the decreasing level of the anesthetic in order to prevent rather than treat pain and swelling. Whether given pre-operatively, before the wearing off of the local anesthetic, or post-operatively ibuprofen can be effective in either scenario.Diflunisal (Dolobid) has shown improved analgesia when compared to aspirin, ibuprofen, naproxen, and indomethacin as well as a lower incidence of side effects in acute post-operative pain.4 It is well-tolerated, but may cause mild irritation of the upper gastrointestinal tract leading to nausea, dyspepsia, and irritation. However, this occurs less frequently than with aspirin or other commonly used NSAIDs. It also demonstrates minimal reversible impairment of platelet aggregation. With a duration of action of 12 hours, much longer than other NSAIDs, it leads to better compliance and fewer doses at just twice daily. However, diflunisal effects are known to begin wearing off around the eighth or ninth hour after administration. This should be kept in mind along with its maximum daily dosage of 1000 mg. The recommended dose is 250-500 mg twice daily with onset of adequate analgesia achieved within the first hour, and peak analgesia achieved in three hours.4 For initial post-operative pain, a 1 g dose can be administered for more rapid onset and peak analgesia times. It would then be followed with the recommended dose. In a study completed by Comfort et al., the efficacy of diflunisal in controlling pain following third molar surgery was compared to acetaminophen 500 mg/codeine 8 mg and etodolac.10 It was found to be both quicker and more effective in controlling pain in the post-operative period.10 Its superior efficacy was believed to be due to its slower rate of absorption via the oral route. It has also been shown that diflunisal inhibits the lipoxygenase pathway which inhibits the production of leukotrienes further decreasing inflammation.9 Like other NSAIDs, diflunisal reversibly inhibits COX-1 and COX-2, thereby triggering anti-platelet action. However, unlike aspirin which is an irreversible inhibitor taking one week to normalize bleeding time, diflunisal only requires 48 hours. The anti-platelet effect is dose dependent and is not affected by twice-daily doses of 250 mg. At 500 mg daily, there is variable platelet aggregation inhibition and by 1 g daily there is consistent inhibition. Diflunisal should be avoided in patients with GERD or various peptic ulcers who are receiving an antacid comprised of aluminum hydroxide as it can reduce the absorption of diflunisal by up to one-third.4
Ketorolac (Toradol) is the most potent NSAID and it has been compared to morphine and meperidine in its analgesic effect.11 The intramuscular route is the most preferable route of administration in doses of 15 mg or 30 mg although it has a lower patient tolerance. Ketorolac causes gastric damage by a dual insult mechanism.10 Not only does it inhibit the production of prostaglandins that support the gastric mucosa like other NSAIDs, but it also causes primary insult due to its acidic nature. When administered via the oral route it should be prescribed in 10 mg tablets taken four times daily with a daily maximum of 40 mg. Evidence supporting ketorolac as superior to other NSAIDs is variable, and it has been observed to be comparable to ibuprofen in some studies. Its contaminant administration with other NSAIDs or aspirin is contraindicated due to the potentiated adverse effects.12 There are certain populations of patients in which NSAIDs are contraindicated. Patients with bleeding disorders, currently on anticoagulants such as warfarin or powerful anti-platelet therapy such as clopidogrel (Plavix) are among these populations. The concern here is not the anti-platelet action of NSAIDs, but that the decreased proliferation of the mucosal lining caused by reduction of prostaglandins can lead to perforation and excessive, even life threatening hemorrhage.8 NSAIDs, not including aspirin, displace anticoagulants from plasma proteins and doubles the risk of bleeding in patients taking clopidogrel, and can double and even quadruple the risk in those taking warfarin. These concerns are magnified in the elderly population. As prostaglandins are essential in renal perfusion, decreased prostaglandin synthesis can lead to nephrotoxicity with higher doses and prolonged use.8 Patients with compromised renal function should not receive NSAIDs for a prolonged period of time. Evidence of nephrotoxicity in patients receiving NSAIDs for five to seven days has not been exhibited.8 Their use should be avoided in patients who have active GI bleeding or peptic ulcers, and it would be prudent to err on the side of caution and to avoid administration to patients with a history of peptic ulcer or GI bleeding. Use of two NSAIDs concomitantly will further increase the risk of side effects.4
Selective COX-2 inhibitors such as celecoxib act similarly however their actions predominantly target the pain, inflammation, and fever effects of the COX pathway. Because they do not interfere with COX-1 they have fewer side effects including gastritis and bleeding, although gastric mucosa protection appears limited. Conversely, by this same principle their use has been controversial due to their implication in the development of myocardial infarction. Furthermore, their effectiveness in pain management appears limited.
NSAIDs + Acetaminophen
The combined use of NSAIDs and acetam
inophen has been shown to have a synergistic effect in dental pain management.3 The combination has greater analgesic activity than NSAIDs alone as shown in 64 percent of studies on their concomitant administration. Combined administration of these drugs should be considered when single drug administration provides inadequate pain relief despite appropriate treatment, and there are no contraindications to administration of either. Combinations of acetaminophen 1000 mg and 400 mg ibuprofen were found to be even more efficacious than if either were combined with codeine 30 mg.14 However, the gastrointestinal tolerance of the concomitant administration of these medications is actually less than either alone and potential side effects should be taken into consideration.7 This combination should only be used post-operatively for a maximum of seven days as long term use is known to be renotoxic.
While the subject of pain management can sometimes seem complex and confusing, it is a necessary consideration in the management of any dental procedure. It is important to note that the experience of pain is multifactorial. Be it chemical, physical or psychosocial factors; all of these contribute to the need for attentive and individualized management plans. It is important to recognize the efficacy of non-opioid treatment options such as acetaminophen and NSAIDs for post-operative pain management as they are essential components of the armamentarium. Further follow-up with each patient to ensure the efficacy of the analgesic plan selected is a key component in patient satisfaction. If the plan that has been selected is ineffective, reach back into your armamentarium for another technique, whether it be a drug in the same category, a combination of NSAIDs and acetaminophen or the addition of an opioid. There are many approaches available in the analgesic armamentarium, and they should be catered to the unique needs of each patient.OH
Dr. Alia El-Mowafy; DDS, MSc Candidate, Dental Anaes. Resident
Dr. Peter Nkansah, DDS, Dip. Anaes., Specialist in Dental Anaes. (Ont).
Alia El-Mowafy attended the Bachelor of Science programme at York University majoring in Psychology and Kinesiology. She went on to complete her degree in Dentistry at Future University in Egypt before joining the Dental Anaesthesiology Specialty programme at the University of Toronto. She is an MSc candidate in Dental Anaesthesiology. Alia had an early start in research as she was an author in two abstracts and a paper. She was also a presenter at the IADR 2010 in Barcelona. She is a member of the American Society of Dental Anaesthesiologists.
Dr. Nkansah is a specialist in Dental Anaesthesia with a private practice in Toronto. He is a member of the editorial board of Oral Health and is an Assistant Professor with the University of Toronto, Western University and Sunnybrook Health Sciences Centre.
Oral Health welcomes this original article.
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