Although the use of long-acting local anesthetics has become a useful therapeutic approach for managing peri- and postoperative pain, recent evidence reveals unexpected outcomes. This article reviews the clinical use of long-acting local anesthetics, presents current clinical research findings, and makes recommendations for their use.
Although the use of long-acting local anesthetics has become a useful therapeutic approach for managing peri- and postoperative pain, recent evidence reveals unexpected outcomes. This article reviews the clinical use of long-acting local anesthetics, presents current clinical research findings, and makes recommendations for their use.
Strategies for perioperative pain management using long-acting local anesthetics
Pharmacologic management of dental pain is accomplished through three general mechanisms: blocking the nociceptive impulse along the peripheral nerve, reducing nociceptive input from the site of injury, or attenuating the perception of pain in the central nervous system (CNS). These strategies can be combined to manage pain throughout the perioperative period.
Blocking Nociceptive Impulse
Stimulation of peripheral nerve endings and accumulation of chemical mediators both directly and indirectly activate nerve endings, resulting in pain. Input along trigeminal nerve pathways is routinely blocked for dental procedures by administering a local anesthetic in the vicinity of the nerve. The duration of pulpal anesthesia of local anesthetic agents such as lidocaine and articaine with epinephrine is from 1 to 2 hours after injection. If the procedure has initiated the cytokine cascade leading to inflammation, the offset of local anesthesia coincides with peak release of pain mediators such as prostaglandins and bradykinin. Administration of a long-acting local anesthetic postpones the onset of sensation and thus the perception of postoperative pain.
Reducing Nociceptive Input from the Site of Injury
Recognition that locally released mediators can activate peripheral nerve endings suggests the therapeutic potential of interfering with the release or actions of these mediators. For example, cytokines and inflammatory mediators such as prostaglandin (PGE 2 ) not only directly signal peripheral nerve endings, they also instigate other inflammatory mediators such as bradykinin to directly activate peripheral nociceptors. Both the direct effects of PGE 2 to signal pain and its ability to magnify the response to other inflammatory mediators intensifies pain sensations. Therefore, drugs that block PGE 2 synthesis or function after tissue injury are effective for reducing inflammatory pain. This information has an important practical application: pretreating patients with anti-inflammatory agents before or soon after dental surgery blocks cyclooxygenase (COX) enzymes before the initiation of tissue damage results in the synthesis of proinflammatory cytokines. This not only has immediate analgesic effects but also blocks the amplification of pain perception, which otherwise can result in increased and prolonged pain. A well-documented strategy for blocking pain in the immediate postoperative period is the administration of anti-inflammatory drugs such as ibuprofen before or immediately after surgery, but before pain onset.
Attenuating the Perception of Pain in the CNS
Once the nociceptive input reaches the CNS, the management of pain becomes more difficult because of the complex modulation and redundant pathways mediating transmission through the CNS. The CNS also reacts to nociceptive input with changes (called sensitization) that lead to the development of increased pain perception, called hyperalgesia, which can prolong pain and result in pain from stimuli that might otherwise not be perceived as painful. Inhibition of these processes has been demonstrated by the preventive use of anti-inflammatory drugs, and these effects are additive if a combination of a nonsteroidal anti-inflammatory drug (NSAID) and long-acting local anesthetic is used to minimize immediate postoperative pain.
Long-acting local anesthetics in perioperative pain management
It is necessary to maintain profound anesthesia when performing dental procedures, and many surgical procedures are lengthy, necessitating a longer duration of action. In addition to the intraoperative nociceptive barrage during the procedure, postoperative pain is a common occurrence following surgical dental procedures due to the resulting tissue injury leading to the release of proinflammatory mediators, cytokine signaling, and inflammatory cell infiltrate. Pain from the surgical incision and tissue manipulation occurs immediately, but gives way to inflammatory pain following inflammatory cell recruitment to the injured area over the course of several hours. Among the multitude of mediators involved in the acute phase response, proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and interleukins (IL-1 β, IL-6, IL-8, and others) are known to play a key role in the inflammatory cascade. It is also well documented that inflammatory mediators increase at the site of tissue injury after dental surgical procedures. Increased expression of proinflammatory cytokines and induction of COX-2, which results in increased prostanoid production 2 to 4 hours after surgery contribute to sensitization, resulting in prolongation of pain.
Pain from surgical treatments arises early in the postoperative period. The pain following endodontic surgical root canal therapy usually reaches its highest peak on the day of surgery after the local anesthesia dissipates, with abatement within 2 to 3 days. Pain from periodontal surgery varies, with mucosal versus osseous procedures having less versus more pain, respectively. Although pain experience after dental surgery is of relatively short duration compared with other surgical procedures, it can have a negative impact on patients’ function and quality of life and negatively affect the perception of dental treatment. Inadequate pain control also leads to prolonged recovery time and poorer patient outcomes. Hence, effective management of postoperative pain is of utmost importance. Long-acting local anesthetics have been recommended for use in the perioperative period, as they are comparable in onset and efficacy to lidocaine, but because of their longer duration, attenuate pain for hours after the procedure, when acute pain is most intense.
Several studies have indicated that administration of long-acting local anesthetics given either before or immediately following surgery can inhibit central sensitization leading to diminution of postoperative pain. Of the long-acting local anesthetics that have been marketed in the United States (ropivacaine, etidocaine, and bupivacaine) currently only bupivacaine is available for use in dental cartridges. Ropivacaine is a relatively new amide agent and is used primarily for epidural blocks. A few studies have demonstrated its efficacy for dental procedures, but it is not used routinely in dental practice because of lack of availability in dental cartridges. Similarly, etidocaine is no longer marketed in the United States.
Bupivacaine
Bupivacaine hydrochloride (1-butyl-2`, 6`-pipeloloxylidide hydrochloride) is a long-acting local anesthetic similar in structure to mepivacaine. It is commercially available as Marcaine (Kodak [Eastman Kodak, Rochester, NY, USA]), and it is formulated in concentrations of 0.25%, 0.5%, and 0.75% with or without epinephrine 1:200,000. The 0.5% concentration of bupivacaine with 1:200,000 epinephrine is available in dental cartridges and is the long-acting local anesthetic most commonly used in dentistry.
The pH of the solution depends on the vasoconstrictor. Bupivacaine solution without epinephrine has a pH of 6.0 to 6.5; with epinephrine, it has a pH of 3.5. Because of its increased lipid solubility and neuronal protein binding, bupivacaine induces local anesthesia lasting 2.5 to 3 times longer than lidocaine. Lidocaine 2% with 1:100,000 epinephrine is a common anesthetic used in dental procedures and is regarded as a standard to which other local anesthetics are compared. When compared with lidocaine, bupivacaine has a relative potency value of approximately 4, meaning that 0.5% solution of bupivacaine is as effective in blocking nerve conduction as 2.0% solution of lidocaine.
Because of its long-lasting effects, bupivacaine is frequently used for dental surgical procedures of long duration, or where inflammation and pain are expected postoperatively. A clinical practice to delay the onset of pain is the injection of bupivacaine at the end of the surgical procedure that was performed with 2% lidocaine with 1:100,000 epinephrine. Lidocaine is often employed to obtain anesthesia for the surgical procedure because of a significant lag in bupivacaine’s onset time seen in some patients, a product of bupivacaine’s slightly higher pKa. It has been shown that when bupivacaine is used at the end of a mandibular periodontal surgical procedure, it provides a significantly greater duration of anesthesia, a reduction in postoperative pain, and a decrease in the amount of opioid analgesics taken compared with the postoperative administration of lidocaine. In the oral surgery model, a reduction in pain in the immediate postoperative period and a decrease in analgesic requirements were demonstrated when 0.5% bupivacaine was injected postoperatively in combination with general anesthesia, with an effect up to 48 hours.
Local anesthetics block the generation and the conduction of nerve impulses by increasing the threshold for electrical excitation in the nerve, thus slowing or eliminating the propagation of the nerve impulse and reducing the rate of rise of the action potential. The efficacy, onset time, and duration of both bupivacaine and lidocaine have been well described for various clinical applications, as summarized in Table 1 . After injection of bupivacaine for peripheral nerve block in people, peak blood levels of bupivacaine are reached in 30 to 45 minutes, with a half-life of 2.7 hours and an anesthetic duration of up to 7 hours depending on injection type.
| 2% Lidocaine 1:100,000 epi | 0.5% Bupivacaine 1:200,000 epi | ||
|---|---|---|---|
| pH | 4.5 (3.3 to 5.5) | 4.0 (3.3–5.5) | |
| pKa | 7.9 | 8.1 | |
| Onset | Infiltration | <2 min | 2–10 min |
| Block | 2–4 min | 2–10 min | |
| Duration | Infiltration | 60 min | 5–6 h |
| Block | 90 min | 5–7 h | |
Long-acting local anesthetics in perioperative pain management
It is necessary to maintain profound anesthesia when performing dental procedures, and many surgical procedures are lengthy, necessitating a longer duration of action. In addition to the intraoperative nociceptive barrage during the procedure, postoperative pain is a common occurrence following surgical dental procedures due to the resulting tissue injury leading to the release of proinflammatory mediators, cytokine signaling, and inflammatory cell infiltrate. Pain from the surgical incision and tissue manipulation occurs immediately, but gives way to inflammatory pain following inflammatory cell recruitment to the injured area over the course of several hours. Among the multitude of mediators involved in the acute phase response, proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and interleukins (IL-1 β, IL-6, IL-8, and others) are known to play a key role in the inflammatory cascade. It is also well documented that inflammatory mediators increase at the site of tissue injury after dental surgical procedures. Increased expression of proinflammatory cytokines and induction of COX-2, which results in increased prostanoid production 2 to 4 hours after surgery contribute to sensitization, resulting in prolongation of pain.
Pain from surgical treatments arises early in the postoperative period. The pain following endodontic surgical root canal therapy usually reaches its highest peak on the day of surgery after the local anesthesia dissipates, with abatement within 2 to 3 days. Pain from periodontal surgery varies, with mucosal versus osseous procedures having less versus more pain, respectively. Although pain experience after dental surgery is of relatively short duration compared with other surgical procedures, it can have a negative impact on patients’ function and quality of life and negatively affect the perception of dental treatment. Inadequate pain control also leads to prolonged recovery time and poorer patient outcomes. Hence, effective management of postoperative pain is of utmost importance. Long-acting local anesthetics have been recommended for use in the perioperative period, as they are comparable in onset and efficacy to lidocaine, but because of their longer duration, attenuate pain for hours after the procedure, when acute pain is most intense.
Several studies have indicated that administration of long-acting local anesthetics given either before or immediately following surgery can inhibit central sensitization leading to diminution of postoperative pain. Of the long-acting local anesthetics that have been marketed in the United States (ropivacaine, etidocaine, and bupivacaine) currently only bupivacaine is available for use in dental cartridges. Ropivacaine is a relatively new amide agent and is used primarily for epidural blocks. A few studies have demonstrated its efficacy for dental procedures, but it is not used routinely in dental practice because of lack of availability in dental cartridges. Similarly, etidocaine is no longer marketed in the United States.
Bupivacaine
Bupivacaine hydrochloride (1-butyl-2`, 6`-pipeloloxylidide hydrochloride) is a long-acting local anesthetic similar in structure to mepivacaine. It is commercially available as Marcaine (Kodak [Eastman Kodak, Rochester, NY, USA]), and it is formulated in concentrations of 0.25%, 0.5%, and 0.75% with or without epinephrine 1:200,000. The 0.5% concentration of bupivacaine with 1:200,000 epinephrine is available in dental cartridges and is the long-acting local anesthetic most commonly used in dentistry.
The pH of the solution depends on the vasoconstrictor. Bupivacaine solution without epinephrine has a pH of 6.0 to 6.5; with epinephrine, it has a pH of 3.5. Because of its increased lipid solubility and neuronal protein binding, bupivacaine induces local anesthesia lasting 2.5 to 3 times longer than lidocaine. Lidocaine 2% with 1:100,000 epinephrine is a common anesthetic used in dental procedures and is regarded as a standard to which other local anesthetics are compared. When compared with lidocaine, bupivacaine has a relative potency value of approximately 4, meaning that 0.5% solution of bupivacaine is as effective in blocking nerve conduction as 2.0% solution of lidocaine.
Because of its long-lasting effects, bupivacaine is frequently used for dental surgical procedures of long duration, or where inflammation and pain are expected postoperatively. A clinical practice to delay the onset of pain is the injection of bupivacaine at the end of the surgical procedure that was performed with 2% lidocaine with 1:100,000 epinephrine. Lidocaine is often employed to obtain anesthesia for the surgical procedure because of a significant lag in bupivacaine’s onset time seen in some patients, a product of bupivacaine’s slightly higher pKa. It has been shown that when bupivacaine is used at the end of a mandibular periodontal surgical procedure, it provides a significantly greater duration of anesthesia, a reduction in postoperative pain, and a decrease in the amount of opioid analgesics taken compared with the postoperative administration of lidocaine. In the oral surgery model, a reduction in pain in the immediate postoperative period and a decrease in analgesic requirements were demonstrated when 0.5% bupivacaine was injected postoperatively in combination with general anesthesia, with an effect up to 48 hours.
Local anesthetics block the generation and the conduction of nerve impulses by increasing the threshold for electrical excitation in the nerve, thus slowing or eliminating the propagation of the nerve impulse and reducing the rate of rise of the action potential. The efficacy, onset time, and duration of both bupivacaine and lidocaine have been well described for various clinical applications, as summarized in Table 1 . After injection of bupivacaine for peripheral nerve block in people, peak blood levels of bupivacaine are reached in 30 to 45 minutes, with a half-life of 2.7 hours and an anesthetic duration of up to 7 hours depending on injection type.
