Pharmacologic treatment of pain

Pharmacologic treatment of pain

1. Nonsteroidal anti-inflammatory drugs (NSAIDs, Table 38.1) can effectively treat mild to moderate pain, particularly pain associated with inflammatory conditions. Drugs classified as NSAIDs have diverse chemical structures, but all share the ability to inhibit the enzyme cyclooxygenase (COX) and thereby inhibit the formation of prostaglandins from arachidonic acid. Combination therapy with the addition of NSAIDs to opioid during the perioperative period can often provide synergistic analgesia and reduce opioid-related side effects. Although it is important to avoid NSAIDs in patient populations at significant risk for toxicity, many patients having surgery can benefit from their addition.
   1. Mechanism of action. The apparent mechanism for analgesia produced by the NSAIDs is the prevention of neuronal sensitization by diminishing prostaglandin production. Type I cyclooxygenase (COX-1) is a constitutively expressed enzyme that is present in varying amounts in most cells at a fairly constant level. COX-1 serves a key role in cellular homeostasis and is the primary form of the enzyme present in platelets, the kidney, stomach, and vascular smooth muscle. COX-2 -selective inhibitors, developed with the goal to reduce side effects such as gastrointestinal (GI) bleeding associated with NSAIDs, have also been associated with a increase in the risk of adverse cardiovascular effects (eg, myocardial infarction and stroke). COX-2 inhibitors should be used with caution when cardiovascular risk factors are present and are contraindicated during coronary artery bypass graft surgery. Celecoxib is now the only available COX-2 inhibitor in the United States. For an overview of the NSAIDs according to their inhibition of COX and their selectivity for the COX-2 isoenzyme, see Table 38.1.
   2. Toxicity from NSAIDs impacts primarily the GI, renal, hematologic, and hepatic systems.
      1. GI system. Dyspepsia is the most common side effect, and nonselective NSAIDs lead to asymptomatic ulcers in 20% to 25% of users within 1 week of administration. Complicated ulcers, including perforated ulcers, upper GI bleeding, and obstruction occur in a significant number of long-term NSAID users. Factors that increase the risk of NSAID-induced GI toxicity are shown in Table 38.2.
      2. Renal impairment occurs in some patients taking NSAIDs and results from reduction in renal perfusion due to inhibition of prostaglandin synthesis. In patients with contraction of their intravascular volume (eg, congestive heart failure, acute blood loss, and hepatic cirrhosis), renal perfusion is maintained through the vasodilatory effects of prostaglandins. Renal toxicity may manifest as acute interstitial nephritis or nephrotic syndrome. Acute renal failure occurs in as many as 5% of patients using NSAIDs; renal impairment typically resolves with the discontinuation of NSAID therapy but, rarely, progresses to end-stage renal disease. Factors that increase the risk of NSAID-induced renal toxicity are shown in Table 38.3.
      3. Hematologic toxicity associated with NSAIDs takes the form of inhibition of normal platelet function. Platelet activation is blocked by the inhibitory effects of NSAIDs on cyclooxygenase and the secondary decrease of prostaglandin conversion to thromboxane A₂ (a platelet activator). Aspirin irreversibly acetylates cyclooxygenase, and thus, the platelet inhibition resulting from aspirin use persists for the 7 to 10 days required for new platelet formation. Nonaspirin NSAIDs induce reversible platelet inhibition that resolves when most of the drug has been eliminated. A recent metanalysis suggests that the effect of ketorolac on platelet function does not necessarily result in clinically appreciable postoperative bleeding.
      4. Hepatic toxicity may also result from NSAID use. Minor elevations in hepatic enzyme levels appear in 1% to 3% of patients. The mechanism appears to be immunologic or metabolic-mediated direct hepatocellular injury, with dose-related toxicity occurring with both acetaminophen and aspirin. Periodic assessment of liver function is recommended in those on long-term NSAID therapy.
      5. Inhibition of normal bone formation has been reported in both clinical and animal models. The clinical relevance to NSAID use in the immediate post–orthopedic surgery period and following acute fractures requires further study; despite the frequent use of NSAIDs to provide analgesia after orthopedic surgery and injury, there is little evidence that they dramatically affect healing.
   3. Clinical uses. NSAIDs are used most widely to treat the pain and inflammation associated with rheumatic and degenerative arthritides. They also serve as a useful adjunct to opioids for providing control of acute pain, often reducing opioid requirements and opioid-related side effects in the postoperative period. Numerous agents are available for oral administration, and several are available without prescription. Thus, they are among the most common first-line analgesics.
   4. Available formulations. Ketorolac and diclofenac are parenteral NSAIDs approved for clinical use in the United States. Both are potent analgesics and antipyretics, and several studies have demonstrated their usefulness in treating moderate postoperative pain. Ketorolac and diclofenac are nonselective NSAIDs, and despite a parenteral form, intravenous administration is still associated with GI toxicity similar to other orally administered NSAIDs. Familiarity with the dosing and administration of several oral NSAIDs as well as the parenteral formulations is an important tool for those treating acute pain. For a summary of comparative efficacy and dosages of commonly used nonopioid analgesics, see Table 38.4.
2. Acetaminophen is a para-aminophenol derivative with analgesic and antipyretic properties similar to NSAIDs. The exact mechanism by which acetaminophen exerts its effects has yet to be fully understood. Acetaminophen does not produce any significant peripheral inhibition of prostaglandin production. Acetaminophen causes no significant GI toxicity or platelet dysfunction, and there are few side effects within the normal dose range. Acetaminophen is entirely metabolized by the liver, and minor metabolites are responsible for the hepatotoxicity associated with overdose. The most common oral analgesics used to treat moderate to severe pain incorporate acetaminophen in combination with one of the opioids. Standing per os, per rectum, or IV dosing of 1 g of acetaminophen every 6 hours (<4 g/d) can be a very useful adjunct in the postoperative setting and can significantly improve pain and reduce opioid requirements.
3. Ketamine is an atypical dissociative anesthetic and potent analgesic that is an N-methyl-d-aspartate receptor (NMDA) receptor antagonist, which may play a role in decreasing central sensitization in the development of chronic pain. In contrast to opioids, spontaneous respiration and airway reflexes are relatively well maintained. Hypersalivation is a common side effect that can be eased by coadministration of an antisialagogue such as glycopyrrolate. Ketamine causes indirect stimulation of the sympathetic nervous system by inducing a catecholamine release. In high doses, ketamine causes a “dissociative” state and is associated with unpleasant side effects such as nightmares, which may be attenuated by concomitant administration of benzodiazepines. Use of ketamine as an adjuvant anesthetic has been shown to result in decreased opioid requirements in the immediate postoperative period in a majority of studies without significant increase in adverse outcomes and is especially useful in the management of perioperative pain in patients on chronic opioid therapy. Ketamine infusions (2.5-10 μg/kg/min) can be used as an intraoperative anesthetic adjunct for pain and has been shown to reduce opiate consumption in complex spine surgery up to 48 hours postoperatively. A Cochrane review of perioperative ketamine demonstrated both reduced pain and opioid consumption, increased time to first analgesic, and decreased postoperative nausea and vomiting, at the consequence of increased dysphoric side effects (hallucinations, unpleasant dreams, nystagmus). Ketamine bolus can also be used in the immediate postoperative period as a rescue analgesic, especially after opioid rescue has failed. Patients should be premedicated with a benzodiazepine to mitigate dysphoria and be monitored on telemetry (bolus 10-30 mg). A Cochrane review reported that 27 of 37 studies also demonstrated a significant reduction in postoperative pain with the use of ketamine.
4. Opiates and opioids. Opiates are among the most universally effective agents available for treating acute pain. Morphine, the prototypical opiate, is derived from the milk of the scored seed pod of the Oriental poppy, Papaver somniferum. Several other compounds can be derived directly through the chemical modification of morphine. Those drugs derived directly from morphine are termed the opiates. Other synthetic compounds have been produced that act via opiate receptors—all compounds that act via opiate receptors are termed the opioids. Although opioids form the cornerstone of effective acute pain management, they have significant side effects, and their long-term effectiveness is limited by tolerance, physical dependence, and the possibility of addiction. Common prescribing practices in the United States have led to an epidemic of prescription opioid misuse and abuse. Overdoses involving opioids killed nearly 47,000 people in 2018, and 32% of those deaths involved prescription opioids. Significant reform in physicians’ prescribing patterns represents the first step in addressing this public health issue. Opioids are extremely useful for treating acute pain; although they are in widespread clinical use, their long-term effectiveness for treating chronic, noncancer pain is less clear.
   1. Metabolism. Following injection, morphine rapidly undergoes hepatic 
conjugation with glucuronic acid; morphine remains largely in the ionized form at physiologic pH and is highly protein bound. The plasma concentration attained after an identical dose of morphine increases progressively with increasing age of patients. The plasma concentration of morphine correlates poorly with its pharmacologic effect. Analgesia and depressed ventilation correlate more closely with the cerebrospinal fluid (CSF) concentration. Of the metabolites morphine-3-glucuronide (M-3-G) and morphine-6-glucuronide (M-6-G), M-6-G, although produced in smaller amounts (a ratio of 1:9 in M-6-G:M-3-G), is pharmacologically active producing both analgesia and respiratory depression via interaction with μ-opioid receptors. As a result, prolonged respiratory depression can occur in patients with renal failure as M-6-G elimination is significantly impaired. Unlike fentanyl, histamine release follows IV morphine administration resulting in a decrease in systemic vascular resistance and blood pressure.
   2. Side effects associated with opioid analgesics
      1. Respiratory depression. Opioids cause a dose-dependent reduction in the responsiveness of the brain stem respiratory centers to increases in arterial carbon dioxide tension (Paco₂) that manifests as a reduction in breathing rate and at high doses, apnea.
      2. Sedation. Mediated through the limbic system.
      3. Pupillary constriction. Excitatory action on the autonomic segment of the Edinger-Westphal nucleus of the occulomotor nerve.
      4. Nausea and vomiting. Direct stimulation of the chemoreceptor trigger zone within the area postrema in the medulla.
      5. Constipation. Reduction in the propulsive peristaltic contractions of the small and large intestines.
      6. Bradycardia. Central stimulation of the vagal nucleus within the medulla.
   3. Tolerance. With continued use of substantial amounts of opioids, larger doses of the drug are required over time to produce the same physiologic effects. This phenomenon is called tolerance and is characteristic of the entire class of opioids.
   4. Physical dependence. The precipitation of a distinct withdrawal (abstinence) syndrome when the opioid is discontinued. Manifestations of opioid withdrawal include diaphoresis, hypertension, tachycardia, abdominal cramping, and nausea and vomiting. Physical dependence occurs in any individual given sufficient doses of opioid for extended periods of time and is not synonymous with the complex disease that is addiction, although it can contribute to the neurobiological mechanisms driving compulsive opioid-seeking behaviors.
   5. Opioid-induced hyperalgesia (OIH). This refers to a paradoxical increase in painful stimuli with opioid administration. This is thought to be secondary to the upregulation of compensatory pain pathways, of which the central glutaminergic system plays a central role. Discerning between OIH and tolerance is challenging, and as such, one must rule out an exacerbation of the patient’s pain syndrome before considering OIH as a contributor. Strategies to address OIH once it occurs include opioid rotation and gradual dose reduction.
   6. Forms of opioids
      1. Oral opioids are common agents used for the control of mild to moderate pain in those who are able to continue oral intake. Many agents are available as combination preparations containing an opioid along with acetaminophen. The duration of analgesic action for the orally administered opioids is similar and in the range of 3 to 4 hours. Commonly used oral opioids are listed in Table 38.5. In those with opioid tolerance or greater than average opioid requirements, oral opioid alone (without acetaminophen) should be used to avoid hepatic toxicity.
      2. Intravenous (IV) opioids. Control of moderate to severe pain or treatment of those who are unable to tolerate oral intake often requires the use of IV opioids. The pharmacokinetic profiles of opioid analgesics administered intramuscularly are similar but somewhat more erratic owing to variations in the muscle blood flow compared with that seen with IV administration; however, there is significant discomfort with intramuscular (IM) administration. There is no maximum dose for any of the pure opioid agonists (either orally or parenterally), and the dose can be increased until acceptable analgesia is produced or intolerable side effects ensue. Patients who require large doses of opioids should be closely monitored during initial dose titration as marked respiratory depression and apnea may occur unexpectedly.
5. Muscle relaxants: Medications used in the treatment of pain associated with musculoskeletal systems and spasms have varying mechanisms of action and unique safety and side-effect profiles. These include but are not limited to GABA-B agonists such as baclofen, α₂-agonists such as tizanidine, 5-HT2 antagonists such as cyclobenazeprine, and even benzodiazpenes such as diazepam. The mechanisms of action, side effects, and suggested dosing can be found in Table 38.6.