5: Pain Physiology, Analgesics, Opioid Dependency Maintenance Therapies, Multimodal Analgesia, and Pain Management Algorithms


Pain Physiology, Analgesics, Opioid Dependency Maintenance Therapies, Multimodal Analgesia, and Pain Management Algorithms



This discussion of the anatomy and physiology of pain will briefly describe the processes that are involved in the generation of acute, chronic, or neuropathic pain sensations. The idea is to provide the practitioner with the basis for the assessment of the type of pain and then to appropriately select interventions for managing the pain effectively.

Nociceptive Pain

Nociception is the normal processing of pain by nociceptors in response to tissue damage and inflammation (noxious stimuli), associated with trauma, surgery, inflammation, infection, and ischemia that could be damaging or potentially damaging to normal tissue. Transduction of pain begins when the free nerve endings (nociceptors) of A-delta and C-fibers of the primary afferent neurons respond to noxious stimuli. The nociceptors are distributed in the somatic structures (skin, superficial tissue, muscles, connective tissue, bones, joints, and blood vessels) and visceral structures (visceral organs such as the liver and the gastrointestinal tract).

A-delta and C Afferent Pain Fibers

The A-delta and C-fibers are associated with different qualities of pain. The myelinated A-delta pain afferent axons are the smallest and slowest of the myelinated axons. A-delta fibers respond to either mechanical or temperature stimuli and produce the acute sensation of sharp, bright pain. The unmyelinated C afferent pain fibers respond to a broad range of painful stimuli, including mechanical, thermal, or metabolic factors. The pain produced is slow, burning, and long lasting.

Generation of Pain Impulse to Noxious Stimuli

There are three categories of noxious stimuli: mechanical (pressure, swelling, abscess, incision, tumor growth), thermal (burn, scald), and chemical (excitatory neurotransmitter, toxic substance, ischaemia, infection).

The cause of stimulation may be internal, such as pressure exerted by a tumor, or external, such as a burn. This noxious stimulation causes a release of chemical mediators from the damaged cells including: bradykinin, histamine, potassium, prostaglandin, serotonin, and substance P. These chemical mediators activate and/or sensitize the nociceptors to the noxious stimuli. In order for a pain impulse to be generated, an exchange of sodium and potassium ions (de-polarization and re-polarization) occurs at the cell membranes. This results in an action potential and generation of a pain impulse.

Acute Pain Transmission

Pain transmission process occurs in the following three stages that occur in sequential order:

  • First stage: The pain impulse is transmitted from the site of transduction along the nociceptor fibers to the dorsal horn in the spinal cord.
  • Second stage: From the spinal cord, the impulse is transmitted to the brain stem.
  • Third stage: From the brain stem, the impulse goes through connections between the thalamus, cortex, and higher levels of the brain.

The A-delta fibers and the C-fibers terminate in the dorsal horn of the spinal cord. There is a synaptic cleft between the terminal ends of the A-delta fibers and the C-fibers and the nociceptive dorsal horn neurons (NDHN).

Excitatory neurotransmitters are then released for the pain impulses to be transmitted across the synaptic cleft to the NDHN and these neurotransmitters then bind to specific receptors in the NDHN. The neurotransmitters released are adenosine triphosphate, glutamate, calcitonin gene-related peptide, bradykinin, nitrous oxide, and substance P.

The pain impulse is then transmitted from the spinal cord to the brain stem and thalamus via two main nociceptive ascending pathways. These are the spinothalamic pathway and the spinoparabrachial pathway. When these impulses arrive in the thalamus they are directed to multiple areas in the brain where they are processed.

Acute Pain Perception

Pain perception is the end result of the neuronal activity of pain transmission, and this is where pain becomes a conscious experience. The multidimensional experience of pain has affective-motivational, sensory-discriminative, emotional, and behavioral components. When the painful stimuli are transmitted to the brain stem and thalamus, multiple cortical areas are activated and the following responses are elicited.

The reticular system: This system is responsible for the autonomic and motor response to pain and for warning the person, for example, to automatically remove a hand from a hot surface when it touches the surface. It also has a role in the affective-motivational response to pain such as looking at and assessing the injury to the hand once it has been removed form the hot surface.

Somatosensory cortex: This area of the brain is involved with the perception and interpretation of sensations. It identifies the intensity, type, and location of the pain sensation and relates the sensation to past experiences, memory, and cognitive activities. It identifies the nature of the stimulus before it triggers responses such as: Where is the pain? How strong is the pain? What does the pain feel like?

Limbic system: This system is responsible for the emotional and behavioral responses to pain including attention, mood, and motivation and also with the processing of pain and past experiences with pain.

Acute Pain Modulation

The modulation of pain involves changing or inhibiting transmission of pain impulses in the spinal cord. The multiple, complex pathways involved in the modulation of pain are referred to as the descending modulatory pain pathways (DMPP), and these can lead to either an increase in the transmission of pain impulses (excitatory) or a decrease in transmission (inhibition). Descending inhibition involves the release of inhibitory neurotransmitters that block or partially block the transmission of pain impulses, thereby producing analgesia. Inhibitory neurotransmitters involved with the modulation of pain include: acetylcholine, endogenous opioids (enkephalins and endorphins), gamma-aminobutyric acid (GABA), neurotensin, norepinephirine (noradrenalin), oxytocin, and serotonin (5-HT).

Endogenous pain modulation helps to explain the wide variations in the perception of pain in different people as individuals produce different amounts of inhibitory neurotransmitters. Endogenous opioids are found throughout the central nervous system (CNS) and prevent the release of some excitatory neurotransmitters, such as substance P, thus inhibiting the transmission of pain impulses.

Chronic Pain

Chronic pain can affect the patient’s quality of life. It can be caused by alterations in nociception, injury, or disease and may result from current or past damage to the peripheral nervous system (PNS), central nervous system (CNS), or it may have no organic cause.

The exact mechanisms involved in the pathophysiology of chronic pain are complex and unclear. It is postulated that following injury, rapid and long-term changes occur in parts of the CNS that are involved in the transmission and modulation of pain. A central mechanism in the spinal cord, referred to as hypersensitivity or hyperexcitability, may occur. This occurs when repeated and prolonged noxious stimulation causes the dorsal horn neurons to transmit progressively increasing numbers of pain impulses.

The patient can feel intense pain in response to a stimulus that is not usually associated with pain, such as touch. This abnormal processing of pain within the PNS and CNS may become independent of the original painful event. In some cases, as with amputation, the original injury may have occurred in the peripheral nerves, but the mechanisms associated with the phantom pain are generated in both the PNS and the CNS.

Neuropathic Pain

Neuropathic pain can be defined as pain triggered or caused by a primary lesion or dysfunction in the nervous system resulting from trauma, such as complex regional pain syndrome or chronic postsurgical pain; infection, such as postherpetic neuralgia; ischemia, such as diabetic neuropathy; cancer; or chemical influence, following chemotherapy. This type of pain is usually less responsive to standard pain medications.

Some types of neuropathic pain may develop when the PNS has become damaged, causing the pain fibers to transmit pain impulses repeatedly and become increasingly sensitive to stimuli. Neuropathic pain is distinctly different from nociceptive pain and is described as burning, dull, aching, tingling, electric shock-like, or shooting.

Physical and Psychological Assessment of Pain

Anxiety and fear are known to activate the pituitary-adrenal axis, resulting in increased pain perception. Patients experiencing chronic nonfacial pain may also have increased pain perception as the brain neurophysiology may be altered in such patients. A fearful and anxious patient experiences increased pain, which can best be alleviated by appropriate stress management during patient care. As previously discussed, pain can exist even in the absence of a physical cause; consequently, pain assessment should address both the physical and the psychological aspects of pain.

The best treatment course for pain management begins with a good understanding of:

  • Characteristic features of the pain, along with the duration, frequency, location, symptoms at onset, pain pattern, and severity/quality of the pain, so that you can better help the patient.
  • Past and current pain medication history: all long-acting analgesics or other interventional modalities need to be factored in the decision-making process if the patient is currently on chronic pain therapy.
  • The patient’s current medical status.
  • The patient’s vital organs status, which includes the status of the liver and the kidneys.
  • Assessment of daily medications for underlying disease states and associated DDIs.
  • The biochemical pathways of pain management.
  • Assessment of the appropriate analgesic dose and type(s) of analgesic(s) that should be dispensed.

Analgesics are a very important adjunct in dentistry to assure quick recovery from pain. It is best to prescribe analgesics for no more than two to three days, and patients experiencing pain beyond three days should be reassessed before any additional analgesics are prescribed. Having a tight hold on the amount of analgesics you dispense keeps drug addicts away from your practice!


Pain control can be achieved using one or more of the following:

  • Nonopioid drugs: acetaminophen, NSAIDS, aspirin, or celecoxib.
  • Opioids: morphine, codeine, oxycodone, hydrocodone, oxymorphone, hydromorphone, methadone, fentanyl, meperidine, pentazocine, buprenorphine, and propoxyphene (now withdrawn from the US market).
  • Nonnarcotic opiate agonist: tramadol (Ultram).
  • Adjuncts: corticosteroids, benzodiazepines, antihistamine H1 blockers, muscle relaxants, tricyclic antidepressants (TCAs), and bisphosphonates.



Nonopioids were formerly known as “nonnarcotic” analgesics and the opioids were formerly known as “narcotics.” Both classes of drugs have varying degrees of central and peripheral action. Nonopioids include acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDS). Both interfere with prostaglandin synthesis and both have a maximum, or ceiling, dose for their analgesic effect. NSAIDS do not cause respiratory depression or impair gastrointestinal motility, so NSAIDS are considered an important component with acetaminophen in multimodal pain management, which is discussed further in this chapter.

Acetaminophen (Tylenol)

Acetaminophen Pharmacology

Acetaminophen or paracetamol, a Pregnancy Category B drug, is also known by its chemical name N-acetyl-p-aminophenol (APAP).

Acetaminophen mechanism of action (MOA): Acetaminophen has both analgesic and antipyretic properties, and although the exact MOA is unclear, it is thought to exert its analgesic activity centrally by inhibiting the synthesis of prostaglandins in the CNS and peripherally by blocking pain impulse generation. It should be noted that the drug has barely any influence on peripheral prostaglandin synthesis, especially within inflamed tissues. Thus, acetaminophen is devoid of peripheral anti-inflammatory effects that NSAIDS have. Acetaminophen also has a serotonergic (5-HT) mechanism and a cannabinoid agonism mechanism, which may contribute to its analgesic effect. The half-life of Tylenol is two to four hours and the therapeutic dose in a patient who is not medically complex is 3 g/day.

Acetaminophen metabolism: Acetaminophen undergoes metabolism in the liver through three pathways: conjugation with glucuronide; conjugation with sulfate; and oxidation via the CYP450 enzyme pathway, primarily involving CYP2E1. More than 90% of an acetaminophen dose is metabolized by the liver to sulfate and glucuronide conjugates, which are water soluble and eliminated in the urine. Conversion to sulfate is the primary pathway until the age of 10–12years. Glucuronidation is the primary pathway in adolescents and adults. Approximately only 2–4% of an acetaminophen dose is inactivated by glutathione and then excreted by the kidneys.

Tylenol Toxicity

Tylenol is the most commonly overdosed medication. Hepatotoxicity with acetaminophen is most pronounced when dosages exceed the recommended 24-hour dosing and the toxic metabolite NAPQI cannot be adequately conjugated. Currently, the main cause of acute liver failure in the United States is acetaminophen overdose, which results in thousands of hospitalizations every year, and the only cure in most cases that are detected early is immediate liver transplant. CYP3A4-induced Tylenol hepatotoxicity occurs from the formation of the reactive and toxic metabolite N-acetyl-benzoquinoneimine (NAPQI). Typically, glutathione binds to NAPQI and excretes NAPQI as nontoxic mercapturate conjugates. When glutathione stores are diminished, NAPQI binds to the liver cells causing hepatic necrosis. The conjugate for NAPQI comes from glycogen, and acetaminophen may be toxic for patients with depleted glycogen stores, due to dieting, anorexia, primary liver disease, or medications toxic to the liver. Alcohol, liver disease, starvation, and protein malnutrition decrease glutathione levels and increase the chances of Tylenol toxicity. Hepatotoxicity due to Tylenol is most pronounced in the fasting patient and patients taking drugs primarily metabolized by the liver. Also, alcohol consumption with Tylenol increases NAPQI production, so alcoholics can overdose even with a therapeutic dose. Acetaminophen use is absolutely contraindicated with alcohol and in the presence of alcohol-associated liver disease.

Patients consuming three or more servings of alcohol per day should take even less than the FDA’s proposed recommended dosage: More than two servings of alcohol per day can increase the risk of liver failure from acetaminophen. Patients who take acetaminophen (Tylenol) in high doses, or simply use it regularly, are also at risk. Therefore, patients suspected of chronic alcoholism should limit their daily acetaminophen intake to below 2g in divided doses, rather than the normal daily maximum of 3g. Also, patients with decreased liver function, kidney disease, hepatitis, malnutrition, AIDS, chronic alcohol abuse, or anorexia nervosa may also be at increased risk for liver failure and death when using Tylenol. Acetaminophen may affect the results of blood glucose tests in diabetics as well.

According to an American Pharmacists Association recent news release, the maximum daily dose for single-ingredient Extra Strength Tylenol (acetaminophen) products sold in the United States has been lowered from 8 tablets, caplets, gelcaps, or tablespoons per day (4,000mg) to 6 per day (3,000mg), and the dosing interval has changed from 2 pills every 4–6hours to 2 pills every 6hours. The FDA has announced that it is taking steps to cut the risk of acetaminophen-associated liver damage and other effects of acetaminophen toxicity. Specifically, the FDA is requesting all makers of prescription products that contain acetaminophen to limit the amount of acetaminophen to 325mg per capsule or tablet. Drug companies have until January 14, 2014, to reduce the amount of acetaminophen in their products to 325mg per capsule or tablet. Tylenol and other acetaminophen-based medications will include warnings that taking more than recommended amounts can cause liver damage, that the products should not be combined with other medications that include acetaminophen, and that acetaminophen is the active ingredient.

Induced acute liver failure resulting from Tylenol toxicity can cause impaired hepatic synthetic function, the extent of which can be judged by monitoring the PT/INR (Table 5.1). The PT/INR is increased when the acutely injured liver is unable to produce clotting factors. The Tylenol toxicity prognosis is good when the PT/INR is normal in the presence of increased ALT and AST. Renal failure, encephalopathy, and cerebral edema can additionally occur with acute liver failure associated with Tylenol toxicity. An immediate liver transplant is the only treatment in such cases.

Table 5.1 Summary: Acute Acetaminophen (Tylenol) Toxicity-Associated Liver Function Test (LFT) Changes

LFT Marker Marker Status
Total Protein Normal
Albumin (A) Normal
Globulin (G) Normal
A:G ratio Normal
ALT/SGPT >10,000 IU/L; rapidly normal on recovery
AST/SGOT Increased, but less than ALT
GGT Normal
Alkaline Phosphatase (AP) Increased
PT/INR Acutely prolonged with liver failure
Total Bilirubin Normal
Direct-B Normal
Indirect-B Normal

Tylenol Toxicity Symptoms and Signs

Tylenol toxicity can present with an irregular pulse, nausea, vomiting, diarrhea, sweating, abdominal pain, seizures, and coma.

Tylenol Toxicity Laboratory Test Assessment

Tylenol toxicity causes an acute rise in the ALT and AST to >10,000 U/L within 24hours after ingestion or within 8–16hours in very severe cases, and peak levels occur at 48–72 hours. As discussed previously, the PT/INR, serum creatinine, and blood urea nitrogen (BUN) levels must also be assessed.

Tylenol Toxicity Treatment

The first step in management of Tylenol toxicity is gastrointestinal decontamination with activated charcoal. N-acetylcysteine (NAC) given PO (oral) or IV (intravenous) is the antidote, and most patients recover if NAC is given within eight hours of ingestion of the toxic dose. Glutathione levels are replaced by the sulfhydryl compounds from NAC causing reversal of the toxicity.

N-acetylcysteine (NAC) dose: Initial dose: 140mg/kg followed by 70mg/kg every 4h × 17 doses, after the initial dose.

Acetaminophen (Tylenol) Dosing: Avoid Alcohol When Using Acetaminophen

1. Normal acetaminophen (Tylenol) dose:

a. Regular strength acetaminophen (Tylenol): 325mg/tablet. Adults and children 12years and older can take 2 tablets every 6hours while symptoms last and the patient should not take more than 8–10 tablets in 24hours.
b. Extra-strength acetaminophen (Tylenol): 500mg/tablet. Adults and children 12years and older can take 2 caplets or gelcaps every 6–8hours while symptoms last and the patient should not take more than 6 caplets or gelcaps in 24hours.
2. Tylenol dose with kidney disease: Tylenol dose must be adjusted in renal failure because metabolites can otherwise accumulate. The maximum daily dose of acetaminophen should be no more than 2 g/day in patients with significantly decreased renal function. Use the following guidelines for dosing with kidney disease:

a. CrCl >50mL/min or serum creatinine <2.0mg/dL: Dose normally as discussed previously.
b. CrCl 10–50mL/min or serum creatinine >2.0mg/dL to predialysis: Prescribe 325–650mg q6–8hours only; dose interval decided according to the severity of underlying kidney disease.
c. CrCl <10mL/min or the renal failure/dialysis patient: Prescribe 325–650mg q8hours only.
3. Tylenol dose with liver disease: Use Tylenol with caution in the presence of hepatic impairment. Cases of hepatotoxicity at daily acetaminophen dosages <3g/day have been reported. Limited, low-dose therapy is usually well tolerated with hepatic disease or cirrhosis. Avoid chronic use in hepatic impairment. The maximum daily dose of acetaminophen should be no more than 2 g/day in patients with cirrhosis or chronic active hepatitis. Use the following guideline for dosing with liver disease:

a. Chronic inactive hepatitis: Give Tylenol 325–650mg q6–8hours; dose interval decided according to the extent of inactivity of underlying liver disease.
b. Chronic active hepatitis or cirrhosis: Give Tylenol 325–650mg q8hours.

IV Acetaminophen

IV Acetaminophen was approved by the FDA in 2010 for postoperative pain management of varying intensities for adults and children, to be used either alone or in combination with opioids either prior to surgery or during the intraoperative period.

IV Acetaminophen Advantages

  • IV acetaminophen does not have a black box warning and it can be used in the pediatric population.
  • It does not cause nausea, vomiting, or respiratory depression, which are typically associated with opioids.
  • It does not affect platelets, nor does it cause gastritis and nephropathy that is occasionally seen with NSAIDS
  • It has few DDIs and is very rapid in onset avoiding first-pass in the liver, thus reducing the potential for hepatotoxicity, and proving to be safe in some patients with underlying liver disease. However, it is contraindicated in patients with severe liver disease.
  • IV acetaminophen can easily be switched to oral acetaminophen once the patient tides over the acute phase.

IV Acetaminophen Vial and Dosing Facts

  • No dose adjustment is needed when converting between oral and IV acetaminophen dosing in adults and adolescents.
  • IV acetaminophen is dispensed as a 100mL single-use vial containing 1,000mg acetaminophen. The contents do not need to be reconstituted. It is given over 15 minutes and is not combined with any other drug, especially drugs like chlorpromazine and diazepam. Once punctured, the dose of IV acetaminophen must be administered within six hours or otherwise discarded.

IV Acetaminophen Adult and Children Dosing

1. Adults and children age ≥13years, weighing ≥50kg: 650mg q6h or 1,000mg q8h, with 1,000mg being the maximum single dose injected.
2. Adults and children age ≥13years, weighing <50kg: 12.5mg/kg q4–6h or 15mg/kg q6h, with 15mg/kg being the maximum single dose injected.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDS)

NSAIDS Overview and Classification

Commonly discussed members in this category are aspirin, Pregnancy Category C; ibuprofen, Pregnancy Category B; naproxen, Pregnancy Category B; and celecoxib, Pregnancy Category C.

NSAIDS Mechanism of Action

Cyclooxygenase (COX) enzyme is responsible for the formation of prostaglandins, prostacyclins, and thromboxane A2, with each being involved in the inflammatory response. Thromboxane A2 is additionally responsible for platelet aggregation. There are two different COX enzymes, COX-1 and COX-2. Both COX-1 and COX-2 convert arachidonic acid to prostaglandin, resulting in pain, fever, and inflammation.

Cyclooxygenase-1 (COX-1) is present in most tissues. COX-1 maintains the normal lining of the stomach and the intestines; it maintains renal perfusion and promotes clotting by maintaining platelet function/cohesiveness. Inhibition of COX-1 is therefore undesirable. Cyclooxygenase-2 (COX-2) is primarily present at sites of inflammation, therefore inhibition of COX-2 is considered desirable.

Nonsteroidal anti-inflammatory drugs (NSAIDS) work by inhibiting prostaglandins. Traditional or “nonselective” NSAIDS, such as ibuprofen and naproxen, inhibit both COX-1 and COX-2. The inhibition of COX-2 accounts for the anti-inflammatory effect of the drugs, whereas the inhibition of COX-1 can lead to NSAIDS-associated toxicity and side effects including ulcers, prolonged bleeding times, and kidney problems.

Aspirin and the traditional NSAIDS very particularly inhibit the vasodilator prostaglandins in the kidneys.

NSAIDS and Vital Organs

NSAIDS are metabolized by the liver via conjugative and oxidation pathways, and patients with liver disease should specifically avoid aspirin and ibuprofen. Some NSAIDS are more hepatotoxic than others. Patients with liver cirrhosis are at increased risk of kidney damage due to NSAIDS. Therefore, NSAIDS should be avoided in patients with cirrhosis.

NSAIDS and Pregnancy

NSAIDS should generally be avoided during pregnancy, especially during the first and third trimesters. There is risk of miscarriage in the first trimester and a risk of premature ductus arteriosus closure in the third trimester. Prostaglandins keep the ductus arteriosus patent in the fetus, and therefore prostaglandins should not be inhibited, especially during the third trimester. If benefits far outweigh the risk and if cleared for use by the obstetrician, ibuprofen or naproxen should not be dispensed for more than 48–72hours. Pregnancy Category B acetaminophen is the safest nonopioid analgesic to rely on as an alternate. Additionally, avoid celecoxib (Celebrex) and Pregnancy Category C/D drugs during pregnancy, and diclofenac potassium (Cataflam) and ketorolac in late pregnancy. Also, NSAIDS can alter the renal cortical function in the mother and decrease the fetal renal output.

NSAIDS Adverse Side Effects

NSAIDS can cause gastric irritability, platelet dysfunction, renal insufficiency, and hepatotoxicity.

Gastric toxicity: The most common adverse effect of NSAIDS is gastric toxicity, and older adults and patients with a history of peptic ulcer disease are at highest risk for this adverse side effect. Prostaglandins also produce compounds that protect the gastric lining. Once absorbed, NSAIDS inhibit prostaglandin synthesis in the gastric mucosa and subsequent distribution to the gastrointestinal wall. Avoid NSAIDS in patients with bleeding disorders.

NSAIDS also excessively increase the risk of gastrointestinal bleeding, when combined with warfarin (Coumadin) or clopidogrel (Plavix). This is an important issue, particularly in the elderly and patients on anticoagulant therapy, including patients on low-dose/81mg aspirin. If a patient is at risk for thrombosis, aspirin should not be withdrawn for dentistry.

Acute renal failure: NSAIDS-associated renal damage is due to selective inhibition of the vasodilator prostaglandins, resulting in unopposed action of vasoconstrictor prostaglandins and consequent reduction in renal blood flow. Short-term (2–3 days), low-dose NSAIDS use does not cause this side effect. The risk of renal toxicity with NSAIDS increases with old age and when used in the presence of renal disease, diuretics, cirrhosis, and other nephrotoxic drugs. Prostaglandins are largely responsible for optimal renal perfusion and function; consequently, chronic NSAIDS use can be associated with nephrotoxicity, particularly in patients with compromised renal function. Acute renal failure has been known to occur within 24hours in patients with renal dysfunction and is known to be even more severe in the presence of acute or chronic volume depletion, cardiac failure, liver cirrhosis, ascites, diabetes, or preexisting hypertension. In the presence of renal disease, if the patient’s physician approves and when absolutely needed, short-acting low-dose NSAIDS can be prescribed for a maximum of two to three days.

Platelet dysfunction: NSAIDS temporarily affect platelet cohesiveness and the platelets regain their cohesiveness once the NSAIDS have cleared the system. NSAIDS can usually be stopped 24hours prior to major surgery, once cleared by the patient’s medical doctor.

Leukotrine overproduction: Aspirin and NSAIDS can cause rhinosinusitis, polyps, and asthma in patients allergic to these medications, by blocking the cyclo-oxygenase-1 enzyme, which triggers an overproduction of leukotrienes. Leukotrienes, in turn, cause bronchoconstriction.


Aspirin is a Pregnancy Category C drug that becomes a Category D drug in the third trimester of pregnancy. Aspirin has an analgesic efficacy equivalent to 5–10mg, IM morphine. When needed, the lowest effective aspirin dose should be used. Aspirin has to be used for several days to maximize effect and achieve optimal plasma levels. Aspirin has analgesic, anti-inflammatory and antipyretic activity. The antipyretic activity is central in action.


Aspirin is mainly metabolized in the liver and excreted through the kidneys. Patients with a creatinine clearance <50mL/min or with serum creatinine >2mg/dL should be given aspirin every six hours (q6h) only. Avoid aspirin use in patients with severe liver disease and in patients on dialysis, with a CrCl <10mL/min.


Aspirin and primary hemostasis: When taken daily, aspirin permanently affects platelet cohesiveness for the entire life span of the platelets, which is 10–14 days. Aspirin-associated platelet effect impacts primary homeostasis, causing a prolonged Bleeding Time (BT). Aspirin does not affect the platelet count, PT/INR, or the APTT.

The patient’s physician must always be contacted prior to any major dental procedure to determine if and when the aspirin can be stopped. Consultation with the MD is absolutely necessary as it is the MD who clearly knows the patient’s risk for thrombosis. In most cases in the past, adult or baby aspirin was usually stopped seven days prior to the major surgical procedure when the risk for thrombosis was minimal. Most physicians now prefer the continuation of low-dose aspirin, as bleeding can very easily be controlled with pressure, local hemostats, and sutures, plus the majority of patients encountered these days are high risk for thrombosis to begin with. In the presence of high daily doses of aspirin for arthritis care aspirin may have to be stopped for ten days, but with MD approval. When stopped, aspirin should be restarted 1–2 days after the procedure, so good primary hemostasis is ensured. Tylenol may be substituted in the interim period for pain control.

Aspirin and ibuprofen combination therapy: When given in combination, some studies have shown ibuprofen to competitively inhibit the anti-platelet action of aspirin, whereas other studies have found thromboxane inhibition by aspirin to be reduced by only 1% after ten days of concurrent ibuprofen use.

Routine low-dose aspirin intake is important for patients at increased risk for thrombosis and this effect of ibuprofen on aspirin is important, no matter how small the risk. It is important to note that the anti-platelet action of aspirin occurs within the hepatic portal system after absorption. So in situations when you have to prescribe ibuprofen, it is best for the patient to take daily aspirin on waking up and delay the intake of ibuprofen by 1–2hours, so optimal aspirin effect occurs. As per FDA documents, if used occasionally, there is only minimal risk that ibuprofen will interfere with the effect of low-dose aspirin. If you need only a single dose of ibuprofen, the FDA recommends the patient take ibuprofen 8hours before or 30 minutes after taking a regular (not enteric-coated) low-dose aspirin. FDA recommendations are only for regular, immediate-release low-dose aspirin (81mg). The ability of ibuprofen to interfere with the anti-clotting effects of enteric-coated aspirin or larger doses of aspirin, such as an adult aspirin (325mg), is not known.

Diclofenac and celecoxib (Celebrex) do not have the ibuprofen-associated interaction with aspirin, so when NSAIDS are absolutely needed in the presence of low dose aspirin, diclofenac and celecoxib are more appropriate to dispense.

Aspirin and pregnancy or lactation: Aspirin is a potent prostaglandin inhibitor and theoretical concern for organogenesis in the first trimester, and premature closure of the ductus arteriosus in the third trimester does exist, just as with other NSAIDS. However, no such cases have been found when aspirin has been used for the prevention of preeclampsia. Aspirin should not be used during the breast-feeding period.


Aspirin is available as an 81mg tablet (baby aspirin) and a 325mg tablet (adult aspirin). Dose: 325–650mg q4–6h PRN, maximum dose: 4 g/day. Reduce the dose in the elderly and avoid in patients with hypoalbuminemia and a CrCl <10mL/min (this is the patient on dialysis).

Ibuprofen and Naproxen

NSAIDS have an analgesic efficacy equivalent to 5–10mg, IM morphine and the lowest effective NSAIDS dose should be used. NSAIDS have to be used for several days to maximize effect and achieve optimal plasma levels. Ibuprofen and naproxen are Pregnancy Category B drugs.


They have analgesic, anti-inflammatory, and antipyretic activity. The antipyretic activity is central in action.


They are mainly metabolized in the liver and excreted through the kidneys. NSAIDS use must be avoided in patients with any form of kidney or liver disease. The clearance of naproxen is decreased in the presence of chronic hepatitis.

Analgesia Dose

1. Ibuprofen (Motrin) dose: 200–400mg PO q4–6h PRN; maximum dose: 1,200 mg/day.
2. Naproxen (Naprosyn) dose: 250–500mg PO q8–12h PRN; maximum dose: 1,500 mg/day.

COX-2 Inhibitors


COX-2 production is induced by inflammation and is associated with pain. COX-2 inhibition has analgesic, anti-inflammatory, and antipyretic activity. The analgesic activity of COX-2 is similar to that of the COX-1 inhibitors. Like the COX-1 inhibitors or traditional NSAIDS, the COX-2 inhibitors also are equally effective in treating inflammation, pain, and fever associated with acute or chronic pain from rheumatoid arthritis and osteoarthritis. Unlike the COX-1 inhibitors, they do not affect the gastric mucosa, but recent studies have shown COX-2 inhibitors promoting platelet aggregation. COX-2 inhibitors are Pregnancy Category C drugs that become Category D drugs with prolonged use or with high dosage. Celecoxib has a sulfa tail that can cause a reaction and it should be avoided in patients with sulfonamide antimicrobial allergy.

Celecoxib (Celebrex) is the only selective COX-2 inhibitor currently available in the United States. Unlike aspirin, which is also an NSAID, COX-2 inhibitors are not effective in preventing strokes and heart attacks in patients with high risk for cardiac disease. All other previously available COX-2 inhibitors have now been withdrawn from the US market because of the increased risk for heart attack and stroke. This warning has now also been added to the prescribing label for celecoxib (Celebrex), so patients are aware.


COX-2 drugs are metabolized in the liver and excreted through the kidneys. They have renal effects similar to the COX-1 inhibitors. COX-2 inhibitors should be avoided in the elderly and in patients with renal, hepatic, or cardiac impairment.


Celecoxib, 100–200mg q12h PRN.

Nonopioid Associated Dental Alerts

  • Postoperative pain management: NSAIDS can significantly reduce postoperative pain and swelling when used preoperatively, prior to prostaglandin synthesis. Prostaglandins already formed are not affected, so it is best to provide NSAIDS either preoperatively or before the local anesthesia numbing effect dissipates. A recent clinical trial showed significant pain reduction in patients with irreversible pulpitis when lornoxicam (but not diclofenac potassium) was given prior to an inferior alveolar block anesthesia injection.
  • NSAIDS and acetaminophen have a ceiling effect as far as analgesia is concerned, and any further increase in dose provides no additional benefit. Generally, the pain-relieving effect does not increase with higher doses; thus, 400mg of Motrin/ibuprofen has just as much pain relief as 800mg of Motrin/ibuprofen. A person is more likely to suffer a significant stomach problem with the higher dose.
  • Higher dosing with any NSAID is needed to achieve anti-inflammatory effect, compared with the dose needed to control pain and fever. Thus 200–400mg ibuprofen every six hours reduces pain and fever, but the patient will need 400–800mg ibuprofen every six to eight hours, if inflammation is to be suppressed. All efforts should be made not to exceed the maximum antipyretic total daily total dose of 1,200mg and the maximum anti-inflamatory daily total dose of 2,400–3,200mg. My suggestion would be to try to stay at 2,400mg/day in divided doses for management of inflammation as much as possible instead of 3,200mg/day, for as short a time as possible (maximum two to three days and consume large amounts of water). This way you will avoid any NSAID-related untoward side effects.
  • Postoperative pain can significantly be reduced using ibuprofen 400mg, diclofenac 50mg, codeine 30–60mg with acetaminophen, oxycodone 10mg with acetaminophen, naproxen 500/550mg, or celecoxib (Celebrex) 400mg. It has been found that NSAIDS are generally better than opioids at routine doses.
  • Patients with poor oral hygiene and cigarette smoking habits experience more pain following dental procedures than those with good oral hygiene or non-smokers.
  • NSAIDS and SSRIs: Short-term or long-term dispensing of NSAIDS in combination with SSRIs should always be avoided. Chronic NSAIDS use in the presence of SSRIs can lead to GI bleeds, especially in patients with preexisting bleeding conditions. The potential interaction between the SSRIs and NSAIDS should also be appreciated, even for short-term postprocedural use.
  • NSAIDS and tricyclic antidepressants: NSAIDS combined with tricyclic antidepressants or anxiolytics, along with psychological support, can be useful in treating persistent facial pain of unknown etiology (PFPUE).
  • CYP2D6 inhibitors and inducers: SSRI antidepressants are potent CYP2D6 inhibitors, thus making codeine less effective when given in combinat/>
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Jan 4, 2015 | Posted by in General Dentistry | Comments Off on 5: Pain Physiology, Analgesics, Opioid Dependency Maintenance Therapies, Multimodal Analgesia, and Pain Management Algorithms
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