Local Anesthetics

Local anesthetics have been commonly used in modern anesthesia practice in order to provide surgical anesthesia or analgesia in the perioperative period. Commonly used local anesthetic agents include chloroprocaine, lidocaine, mepivacaine, ropivacaine, and bupivacaine. They are generally administered via perineural, intrathecal, epidural, and intravenous (in the case of lidocaine) routes. They work by blocking the sodium channels on nerves, resulting in reduced propagation of nerve conduction, ultimately leading to both motor and sensory block. In addition, adjuncts to local anesthesia, such as epinephrine and dexmedetomidine, can prolong the duration of nerve blockade and will be discussed in further detail later in this chapter.

Recently, novel formulations of local anesthetics have allowed them to have a prolonged effect. These drugs were created in an effort to reduce both postoperative and, to a larger extent, total perioperative opioid use, with the aim to reduce the risk of postoperative opioid dependence and abuse. Liposomal bupivacaine was introduced with a lipid shell surrounding bupivacaine, which allows a slow release of bupivacaine, thus resulting in a delayed onset, but theoretically in prolonged nerve blockade. It was initially marketed to provide between 24 and 72 hours of pain relief. However, this has had a varied response among patients. Currently, this drug is only approved by the Food and Drug Administration (FDA) for interscalene brachial plexus blocks and field blocks. However, many clinicians have used this drug for off-label uses. More novel than this is HTX-011, a polymer of meloxicam and bupivacaine, with laboratory studies showing both drugs having a synergistic effect between the two drugs and possibly providing up to 72 hours of postoperative pain relief after surgery. Currently, this drug is undergoing clinical trials and has been used for buniectomy, herniorrhaphy, and total knee arthroplasty, and has been shown to reduce perioperative opioid requirements and reduced postoperative pain scores, when compared to the control.

Overdose of local anesthetics via epidural and intrathecal use can lead to a high block, resulting in hypotension and bradycardia, with possible cardiopulmonary collapse. If local anesthetics are administered in large enough quantities, local anesthetic systemic toxicity (LAST) may occur, especially if accidental intravascular administration occurs. Signs and symptoms of LAST include tinnitus, altered mental status, malignant ventricular arrhythmias, and respiratory depression, with severe cases leading to cardiopulmonary collapse. The American Society of Regional Anesthesia and Pain Medicine (ASRA) has a protocol for LAST and LAST-related events. Of all the local anesthetics listed, bupivacaine and ropivacaine are the most cardiotoxic of these. Care must be taken to avoid accidental intravascular administration.

Lidocaine, due to its short half-life and high hepatic extraction ratio and rapid clearance, is currently the only local anesthetic that can be administered via continuous intravenous infusion. Intravenous infusions of lidocaine have been used to reduce perioperative opioid consumption in patients who have difficulties in pain management, such as those with chronic pain syndromes and patients with a history of opiate abuse. Lidocaine infusion may be started pre-, intra-, or postoperatively, with continuous monitoring throughout the duration of the infusion for signs and symptoms of LAST.

Opiates

Opiates used for acute perioperative pain management include morphine, hydromorphone, fentanyl, buprenorphine, methadone, remifentanil, sufentanil, alfentanil, and ketamine. These medications can be administered via oral, intravenous, sublingual, intramuscular, and rectal administration. All of these medications provide excellent analgesia. However, numerous unwanted side effects, as well as significant abuse potential, have prevented successful management of perioperative pain due to secondary sequelae and patient dissatisfaction. Adverse side effects include nausea, vomiting, sedation, opioid-induced respiratory depression, opioid-induced constipation, opioid-induced pruritus, and urinary retention.

Morphine is the most commonly used opiate and was one of the first opiates utilized in clinical practice. It can be administered via numerous routes, with intravenous, intramuscular, and intrathecal, as well as oral, routes being the most popular. It is fast-acting and provides effective analgesia for patients. Intrathecal administration, especially in parturients, provides postoperative analgesia for cesarean sections for up to 24 hours and can also be used in intrathecal pumps in providing chronic pain management in cancer patients. Oral formulations are used to treat chronic pain, especially cancer pain in patients who have severe intractable pain.

Methadone is generally administered to patients who have a history of opiate abuse and are attempting to overcome their addiction. In addition, it can also be used as part of an anesthetic plan to reduce perioperative pain. This drug is generally administered orally or intravenously. Administration of methadone in particular can prolong the QTc interval and can lead to torsades de pointes, which may result in ventricular tachycardia and fibrillation in patients with a history of prolonged QT interval.

Remifentanil may be used as a continuous intravenous infusion at a low rate with a patient-controlled bolus, as part of patient-controlled analgesia (PCA) for acute pain management, in particular for parturients who are not candidates for neuraxial analgesia. Remifentanil is unique of all the opiates in that it has a very short half-life and a context-sensitive half-time of approximately 10 minutes, resulting in complete clearance of the opiate from blood. This is due to the fact that it is metabolized by red blood cell esterases which rapidly break down the drug in the bloodstream.

Sufentanil may be given by neuraxial administration or via an intravenous route (as a bolus or continuous infusion) for acute pain management. It is an excellent adjuvant in local anesthetic solutions for neuraxial analgesia, and has also been used as an adjuvant to prolong the duration of a spinal anesthetic when used for surgical anesthesia. However, it is associated with opioid-induced pruritus, nausea, and vomiting when used as an intrathecal adjuvant. Sufentanil when used as an infusion has a longer context-sensitive half-time, when compared to remifentanil, and care must be taken with regard to administration of large doses of this medication.

Ketamine is another commonly used analgesic in the perioperative period. It can be administered mainly via the intravenous (bolus or continuous infusion), intramuscular, oral, sublingual, and intranasal routes, and has its action on the N-methyl-D-aspartate (NMDA) receptor as an NMDA antagonist. Its use in pain management is generally by continuous infusion, as it reduces the perioperative consumption of opiates in patients, and is generally employed in patients who have difficulties in pain management, such as those who have chronic pain conditions, as well as patients with a history of opiate abuse.

Buprenorphine is another medication used in the perioperative period in patients with a history of opiate abuse. It is generally combined with naloxone to produce buprenorphine/naloxone (naloxone added to reduce the abuse potential of this drug). It is a partial opioid agonist that provides a ceiling effect with regard to analgesia and does not produce as much respiratory depression compared to more potent opiates. This drug is commonly used for withdrawal of opiates in those who have a history of opiate abuse and is generally administered as an oral formulation and, in some instances, as a transdermal patch for this purpose. In addition, it can be combined within local anesthetic solutions as an adjuvant due to the fact that it possesses some local anesthetic properties by blocking voltage-gated sodium channels and can thus be administered via the epidural or intrathecal route.

Meperidine is an opioid with an atropine-like structure with local anesthetic-like properties. Meperidine has been used intrathecally to prolong the duration of spinal anesthesia. However, it has unpleasant side effects, including opioid-induced pruritus, constipation, sedation, nausea, and vomiting. When compared to other commercially available opioids used as adjuvants in intrathecal local anesthetic solutions, meperidine has a greater rate of side effects. Currently, meperidine is most commonly used in the postoperative care unit for the treatment of postoperative shivering. In addition, intrathecal meperidine is associated with a decreased rate of postoperative shivering.

Tramadol is an opiate with both serotonin and norepinephrine reuptake inhibitor properties that can be given via oral, intravenous, intramuscular, and intrathecal administration. Side effects include increased risk of seizures in those with a history of seizures and increased risk of serotonin syndrome (especially in patients who take medications that increase serotonin levels). Intrathecal administration of tramadol, when compared to intrathecal fentanyl, for parturients undergoing cesarean section results in a prolonged duration of spinal block and a reduced incidence of shivering.

Hydrocodone has also been used for acute pain management, especially in the perioperative period. It is a powerful analgesic that is prescribed orally; it provides pain relief for a few hours and should be administered with care. Hydrocodone is generally combined with acetaminophen and is used as part of a multimodal pain regimen. Care must be taken in patients with compromised liver function, as well as in patients who have also been taking acetaminophen separately from this medication, as this can lead to liver toxicity.

Hydromorphone is another powerful analgesic used to treat moderate to severe pain, most commonly given via the intravenous and intramuscular, as well as oral, routes. Hydromorphone has a quick onset and a short duration of action, making it effective for titration in the perioperative period. Intravenous use is most commonly given in the perioperative period either in divided doses administered by healthcare personnel or as a patient-controlled infusion. It is used as part of a multimodal pain regimen, as the drug has significant side effects with a high risk of abuse potential.

Nonsteroidal Antiinflammatory Agents

These medications inhibit the cyclooxygenase (COX) enzymes, of which there are two main types related to pain – COX-1 and 2. These medications work by reducing inflammatory mediators that provide nociceptive pain. They provide excellent analgesia, especially when incorporated within a multimodal analgesia regimen. It must be noted that these particular agents have a ceiling effect with regard to analgesia. Side effects include nausea, vomiting, gastrointestinal bleeding, increased risk of cardiovascular disease (especially in COX-2-selective nonsteroidal antiinflammatory drugs (NSAIDs)), platelet dysfunction, and increased risk of bleeding and renal dysfunction. Most clinicians tend to avoid these medications in patients who have had a history of gastrointestinal bleeding and renal disease, in order to prevent worsening of the disease. As mentioned earlier in this chapter, meloxicam, an NSAID, has been combined with bupivacaine to produce an extended duration of analgesia.