Opioids

Opioids including morphine, hydromorphone, and fentanyl have been the cornerstone of effective burn pain management for decades. They are widely available, can be administered by a variety of routes (e.g., oral [PO], intravenous [IV], transdermal) are inexpensive, and have a relatively ubiquitous familiarity among health care providers. In experimental studies utilizing burn injury, opioids (µ-receptor agonists) have been shown to produce antinociceptive effects, although there may be reduced efficacy of morphine antinociception in chronic burn injury. Opioid doses required by patients in the acute phase of burn injury to control pain may be many times greater than maximum recommended doses. An early negative consequence of (and possibly result from) this rapid and massive dose escalation is the development of acute opioid tolerance. A later consequence of this opioid escalation may be opioid-induced hyperalgesia. Longer-acting opioids, such as methadone, may mitigate or even reverse this acute tolerance and hyperalgesia, as might using other nonopioid analgesics, including ketamine, dextromethorphan, and clonidine. Although opioids are an important modality for the treatment of burn pain, clinicians should be aware of the side effects (including respiratory depression and hyperalgesia) associated with their use in any patient. For burn patients, the immunosuppressant effects of opioids could theoretically lead to an increase risk of infectious complications, although opioids should not be withheld in patients with burn-related pain.

Methadone is a unique opioid because of its receptor binding properties. It is both a mu-opioid and N -methyl- d -aspartate (NMDA)-receptor antagonist, and it also has serotonin and norepinephrine reuptake inhibitor properties. Administration can occur via oral, parenteral, and rectal routes. However, because of variable and unpredictable potency, dosing efficacy is dependent on chronicity. The long-acting analgesia provided by methadone makes this an ideal opioid for maintenance in burn pain management. Further, the NMDA antagonist properties may be responsible for reducing or reversing opioid tolerance and hyperalgesia from other shorter-acting opioids, as well as modulating neuropathic pain. Methadone may be a viable option for some burn patients who are opioid tolerant and have developed chronic neuropathic pain unrelieved by conventional pharmacotherapies.

Fentanyl is a synthetic lipophilic opioid analog with high potency. These properties facilitate rapid onset of action and quick redistribution from the central circulation. Lipophilicity allows for transmucosal absorption via nasal or buccal routes with rapid onset and peak effect similar to that achieved by IV administration. Although fentanyl is generally administered intravenously, it can be given orally or intranasally. These properties make this opioid a useful adjunct for procedural burn care activities, such as dressing changes and hydrotherapy. The use of oral transmucosal fentanyl citrate and patient-controlled intranasal fentanyl for procedural wound care in burn patients has been reported.

N -Methyl- d -Aspartate (NMDA)-Receptor Antagonists

NMDA antagonists such as ketamine and dextromethorphan may be valuable agents for the treatment of burn pain, as the NMDA receptor plays a central role in neuropathic pain processing and tolerance. In an experimental human study, ketamine significantly reduced the area of secondary hyperalgesia resulting from local first-degree burn injury. Similarly, dextromethorphan reduced the magnitude of secondary hyperalgesia from experimentally produced burn injuries.

Ketamine is a noncompetitive NMDA-receptor antagonist with antihyperalgesia and anti-allodynia properties. It reduces NMDA-R–mediated central transmission and processing of pain, thereby inhibiting central wind-up. Thus, there are many benefits to initiating ketamine early in the course of burn wound care. When administered with opioids, ketamine has synergistic effects with superior pain relief and reduced opioid consumption compared to placebo. When administered with opioids, ketamine appears to have a synergistic analgesic effect on experimentally induced wind-up–like pain in humans. At analgesic doses, it has significantly less risk of respiratory depression and negligible psychomimetic or dissociative effects. Analgesic maintenance dosing ranges from about 1 to 3 mcg/kg/min (or 0.05 to 0.15 mg/kg/hr or 4 to 10 mg/hr). Furthermore, there appears to be no risk of developing tolerance to the drug, even with extended-duration infusion at analgesic doses. A survey of 188 European burn centers noted that ketamine was preferred for analgesia in 12% and for sedation in 13% of all substances used. A systematic review of studies investigating intravenous ketamine as an analgesic agent for burn pain suggested that ketamine demonstrated analgesic efficacy for burn injuries with attenuation of secondary hyperalgesia and that no subjects withdrew from the studies as a result of ketamine-related side effects. Delivery of ketamine via patient-controlled analgesia for burn dressing changes has been reported. Ketamine has been used for long-term sedation and analgesia in burn patients. Finally, ketamine may be an effective analgesic agent for painful procedures in the pediatric burn patient.

Dextromethorphan (DXM) is a noncompetitive NMDA-receptor antagonist that acts by reducing excitatory transmission of primary afferent pathways and is effective in managing challenging neuropathic/wind-up pain in patients who, for a variety of reasons, may be unable to receive ketamine. It has a reduced affinity for the NMDA-receptor compared to ketamine, and it also has a significant first-pass effect in the liver via CYP2D6 microsomal enzymes. Clinically, DXM has synergistic effects when administered with opioids and has superior analgesic and opioid-reducing effects when compared to placebo. Most studies describe doses in the 60 mg twice a day to 90 mg three times a day range. It is effective in 70% to 90% of patients but has been shown to have better efficacy at lower doses when coadministered with a CYP2D6-inhibitor such as quinidine. There are virtually no psychomimetic effects at the doses used clinically. Clinically, however, ketamine appears to be used more frequently than dextromethorphan.

Nonsteroidal Anti-Inflammatory Agents (NSAID s )

Analgesia from nonsteroidal anti-inflammatory drugs (NSAIDs) occurs by reducing inflammation and inflammatory mediators via cyclooxygenase-specific inhibition (COX-1 and COX-2). In the burn trauma population, NSAIDs may be useful adjuncts to help reduce the neurogenic inflammatory pain and fever associated with burns. In the acute setting, however, their use should be time and dose limited as they may present increased risks of bleeding from platelet dysfunction, gastric ulcers and gastrointestinal bleeding from COX-1 inhibition in the setting of acute stress, and renal dysfunction in the setting of reduced renal perfusion, especially in patients with larger total body surface area (TBSA) burns. COX-2–specific inhibitors (i.e., celecoxib) may offer a better overall safety profile compared to nonspecific COX inhibitors like ibuprofen and ketorolac, but data in the burn patient population are lacking and the subject needs to be better studied. NSAIDs may be especially useful for the treatment of burn pain, as experimental studies suggest that intrathecal or local administration of NSAIDs may decrease postburn hyperalgesia and reduce hypersensitivity in skin sensitized by ultraviolet burn. Intravenous ketorolac administered to volunteers increased the pressure pain tolerance threshold and attenuated secondary hyperalgesia from an experimental skin burn injury. In addition, experimental animal studies suggest that NSAIDs may enhance tissue perfusion and reduce edema formation after burns. Few studies have specifically examined NSAIDs or acetaminophen alone in the treatment of burn pain as the majority of these agents have been used as part of a multimodal approach to pain management in burn patients. A prospective, multicenter, randomized, double-blind trial evaluating intravenous ibuprofen for treatment of fever and pain in burn patients found that use of intravenous ibuprofen was associated with a significant reduction in fever and that use of the maximum daily recommended dose (800 mg every 6 hours) over 5 days was well tolerated. Finally, acetaminophen (also called paracetamol, or APAP) may be useful in the management of background postburn pain in children at doses in the 10- to 15-mg/kg/4 hr range. It is available for administration via oral, rectal, and intravenous routes. In one observational study 50% of children received only acetaminophen to control background pain.

Gabapentinoids

The gabapentinoids gabapentin and pregabalin are lipophilic structural analogs of γ-amino butyric acid (GABA) that selectively block Ca ²⁺ channels containing the α ₂ δ-1 subunit. In injured dorsal root ganglion neurons, gabapentin has been shown to selectively silence spontaneous discharges but failed to block propagation of normal impulses. In peripheral nerve injury, as occurs in burn trauma, gabapentin activates and enhances the efficacy and release of descending noradrenergic neuronal activity from the locus coeruleus. By using central neuronal plasticity, it induces more spinal noradrenaline release after nerve injury, suppresses transmission of pain signals to the brain, and may facilitate a more natural sleeplike state in the acute setting owing to the upregulation of activity in the locus coeruleus. Gabapentinoids may be effective for the treatment of burn pain, as experimental studies demonstrate that oral gabapentin (in humans) may decrease primary mechanical allodynia in acute inflammation following a thermal injury and that intrathecal gabapentin (in rats) may produce a dose-dependent reversal of thermal hyperalgesia evoked by mild thermal injury.

Despite the potential benefits of gabapentinoids in the treatment of burn pain especially considering the presence of neuropathic pain in burn patients, few studies have actually been undertaken to examine the analgesic efficacy of this modality. One of the few double-blind, randomized placebo-controlled trials examining the analgesic efficacy of pregabalin found that administration of pregabalin (up to 300 mg twice a day over a period of 28 days) significantly reduced several aspects of the neuropathic pain and pain associated with procedures. A relatively small retrospective review of pregabalin noted that 69% of patients in a burn outpatient clinic experienced some reduction in pain score after treatment with pregabalin. Observational data also suggest that gabapentin may be useful in reducing neuropathic burn-related pain, as administration of gabapentin rapidly reduced the severity of the neuropathic burn pain and decreased opioid consumption. Another potentially useful role for gabapentin is for the treatment of postburn pruritus in patients where pruritus is not relieved with antihistamines.

N a ⁺ -Channel Blockers: Local Anesthetics

Sodium channel blockers such as local anesthetics have been shown to reduce primary and secondary hyperalgesia from experimental heat trauma in humans. Human experimental studies indicate that intravenous lidocaine may attenuate long-term inflammation-induced tissue responses to thermal injury, and it has been shown to attenuate cytokine-induced cell injury in endothelial and vascular smooth muscle cells. Local anesthetics for analgesia can be administered via nerve blocks or intravenously in some cases.

Intravenous lidocaine has been used as an analgesic agent for postoperative pain control and for the treatment of neuropathic pain. There is only one randomized controlled trial and a few observational reports describing the use of intravenous lidocaine for the treatment of burn pain. The sole randomized controlled trial examined intravenous lidocaine (versus placebo) in 45 severely burned patients undergoing wound care procedures on two consecutive days. Subjects were randomized to either the intravenous lidocaine or control on the first dressing day and crossed over to the alternate treatment on the second dressing day. Although pain scores were significantly lower for lidocaine, there were no significant differences with regard to opioid consumption or satisfaction. A systematic Cochrane review was unable to recommend routine use of intravenous lidocaine in burn pain management at this time.

Neuraxial and peripheral regional nerve blockade have been used as analgesic techniques in the treatment of postoperative pain; however, these techniques have not been widely used for the treatment of burn pain. A variety of single-injection regional analgesic techniques have been described in burn patients, typically for reducing pain at skin graft donor site. One case report described using double continuous peripheral nerve block catheters in a child who had suffered a burn injury. Despite the potential benefits that peripheral and neuraxial catheter blocks can offer, clinicians should be aware of the potential infectious complications associated with continuous regional analgesic techniques, especially if indwelling catheters are used for any duration.

α ₂ -Adrenergic Agonists

Clonidine and dexmedetomidine are both highly selective central and peripheral α ₂ -adrenergic agonists that decrease noradrenaline release at presynaptic receptor sites causing sympatholysis, thereby reducing autonomic outflow. Both drugs significantly reduce pain intensity and have a morphine-sparing effect. Other potential benefits include anti-inflammatory effects, improved macrophage function, antiapoptotic activity, reduced delirium, and reduced mortality by approximately ~70% for dexmedetomidine when compared to using benzodiazepines for sedation in critically ill patients. Analgesic dosing for these agents depends on the route of administration. For clonidine, dosing regimens may include 2 to 5 mcg/kg PO, 0.1 to 0.3 mg/24 hr TTD, or 30 mcg to 300 mcg IV for procedural sedation in chronic opioid/chronic pain patients. Dexmedetomidine is given exclusively IV as an infusion at 0.2 to 1 mcg/kg/hr but may be bolused intermittently in small doses of 4 to 8 mcg IV push with minimal side effects. In terms of nociception, α ₂ -adrenergic agonists may have a role in the prevention or treatment of burn pain. Experimental data suggest that α ₂ -adrenoceptor-mediated mechanisms may be involved in nociceptor sensitization to heat stimuli in normal skin and produce antinociceptive effects in a thermal hyperalgesia model. Clinically, α ₂ -adrenergic agonists may be used for analgesia and sedation in burn patients. A report of oral clonidine in a burn patient who had severe pain noted that administration of clonidine resulted in improved analgesia and sedation. The addition of low-dose intravenous clonidine in a child with severe burns requiring large doses of morphine causing severe opioid-related side effects resulted in a significant decrease in morphine consumption with attendant improvement in ventilatory, gastrointestinal and psychological functions. When administered to burn patients, dexmedetomidine is typically used for sedation for procedures or in critically ill mechanically ventilated patients.