Inpatient Pain Management

The acute phase of burn pain management generally takes place in an inpatient setting. In a burn patient, the experience of pain is that of a chronic baseline pain negatively accentuated by frequent procedures such as surgeries, dressing changes, and procedures. Periprocedural pain often escalates, requiring an individualized treatment plan involving continuous monitoring, reassessment, and analgesic dose adjustments. In addition to this constant nociceptive input, the anticipation of pain leads to psychological trauma, which further intensifies the pain perception. Perioperative and periprocedural pain management is important because adequate pain management decreases morbidity and mortality, as well as the likelihood of development of persistent postoperative pain. Inadequate pain control is also associated with a wide range of psychiatric conditions, including post-traumatic stress disorder (PTSD), depression, anxiety, and sleep disorders. Effective analgesia facilitates patient participation in rehabilitation and recovery.

Tolerance and Opioid-Induced Hyperalgesia

With prolonged opioid use, changes in the central nervous system occur, leading to a decrease in analgesic responsiveness to opioids. This process is referred to as tolerance. Tolerance can occur during the hospitalization period and in some patients as rapidly as within the perioperative period. Studies suggest that tolerance can occur even with an intraoperative infusion of a short-acting opioid. Tolerance is well known to occur in patients on chronic opioid therapy; however, it can also occur in opioid-naïve patients who are acutely exposed to opioids. Tolerance partially explains the need for dose escalation. Although tolerance to the analgesic effects of opioids occurs, tolerance to certain side effects, such as constipation or itching, does not develop.

Tolerance can be confused with opioid-induced hyperalgesia (OIH), which is defined as intensification of pain in the context of opioid use. In OIH, nociceptors become sensitized as a result of exposure to opioids. Patients can experience increased pain from painful and nonpainful stimuli (hyperalgesia and allodynia, respectively). OIH may occur irrespective of duration of opioid exposure or opioid dose. There is growing evidence that ultrashort-acting opioids, such as remifentanil, may induce this phenomenon and perhaps should be avoided in burn injury patients. Opioid dose reduction can be helpful in improving analgesia but is a difficult therapy for patients to accept.

Clinically, both tolerance and OIH manifest as an intensification of the patient’s pain experience, suggesting a need for opioid dose escalation. This can further be confused with pseudoaddiction, which appears as opioid-seeking behavior but is a result of inadequate pain control rather than addiction.

Ultimately, it is important to recognize that burn patients’ opioid requirements, especially for patients who were previously on opioid therapy, substantially exceed standard dosing recommendations. Identification of patients with a history of long-term opioid use early in course of treatment ensures proper opioid dosing and better analgesic success. Although identification of opioid tolerance in trauma patients may be challenging due to inability to communicate, the patient’s family, primary care provider, and review of controlled substance database and toxicology screen can be helpful.

Patient-Controlled Analgesia

The most common route of opioid administration in the immediate postburn injury period is IV. Opioids may be administered either as nurse-administered boluses, or via a patient-controlled analgesia (PCA) device. For severely critically ill patients, the route of delivery is generally through a continuous IV infusion because patients are often incapacitated and unconscious. Continuous opioid infusions are appropriate in patients who are in an intensive care unit setting where the risk of opioid-related respiratory depression is continuously monitored. This form of administration should be used with great caution in unmonitored settings.

One of the most common methods of IV opioid administration to burn patients is via a PCA. This form of delivery has the benefit of flexible administration, circumventing delays associated with nursing care, and overall contributing to improved patient satisfaction. When dosed appropriately, PCA is immediate, safe, and efficacious, leading to a sense of control and empowerment thus decreasing anxiety. PCA analgesia can be particularly valuable during dressing changes and PT. Similar to other opioid formulations, effectiveness of PCA depends not only on proper PCA prescription (bolus dose, frequency of administration, and lockout interval) but, perhaps more importantly, on regular monitoring of patient’s analgesic response and frequent dose adjustments. When determining proper opioid dosing, one should consider that chronic opioid users are thought to require, on average, 3 to 4 times more daily morphine milliequivalents than opioid-naïve patients.

Opioids administered via PCA are thought to be less likely associated with risk of inadvertent respiratory depression or overdose; however, PCA use is not void of complications. Most PCA-related incidents are secondary to inappropriate PCA technique understanding by the patient, opioid dose administration by individuals other than the patient, or erroneous PCA prescription or programming. In addition, most PCA overdose incidents occur among patients receiving concurrent baseline opioid infusion and/or treatment with other sedatives (ie, benzodiazepines).

In most cases, baseline infusions are not recommended because they are associated with increased risk of side effects and overall escalation in opioid use, with no notable improvement in analgesia. Exceptions may apply to some opioid-tolerant patients with high daily opioid requirements who often need substantial and rapid PCA opioid dose escalation, which predisposes them to the sedative effects, in particular when combined with other respiratory depressants, such as benzodiazepines.

To achieve optimal analgesic efficacy and safety, PCA opioid administration should be individualized. Consideration should be given to the patient’s age, weight, health status, opioid tolerance, extent of injuries, and coexisting comorbidities (eg, history of apnea, respiratory conditions, renal or hepatic impairment). The PCA should be viewed as a method of delivering analgesia for breakthrough pain. Additional time-released opioid medications should be concurrently provided to achieve continuous therapeutic serum opioid levels, without the need for unremitting PCA use. This approach allows for PCA-free time, such as during rest or sleep. Initiation of PCA must be preceded by an opioid bolus in an effort to quickly achieve therapeutic serum levels required for adequate analgesia. Repeat boluses may be further required after prolonged periods of decreased PCA use (on awakening) or at a time of increased analgesic need (eg, dressing changes, PT).

Treatment of Patients on Buprenorphine Therapy

Buprenorphine is used to treat opioid addiction. It is available in a sublingual form as Subutex and, to deter from misuse, it is also available in a formulation with naloxone as Suboxone. It is a partial mu agonist, with strong affinity to the mu-opioid receptor. As a result, it only partially activates the mu-receptor and also makes it more difficult for other mu agonists (opioids) to fully activate the receptor. In patients on buprenorphine therapy, the analgesic effect of other opioids is attenuated.

This poses a problem for a patient who is on Suboxone or Subutex and unexpectedly presents with an acute injury. In such a situation, the authors’ recommendation is to continue buprenorphine therapy only if the degree of injury is mild and recovery is expected to be quick and not particularly painful. It is imperative to recognize that patients who are maintained on buprenorphine will require much higher doses of a full opioid agonist to obtain analgesia.

If the injury or the healing process is anticipated to be prolonged and painful, it is best to discontinue buprenorphine therapy and treat with a full opioid agonist for pain.

Another alternative is to use buprenorphine as an analgesic. This is best for situations in which pain associated with the injury is mild to moderate because, as mentioned previously, buprenorphine is a partial agonist and, as a result, there is a ceiling effect to the analgesic properties. Buprenorphine maintains an analgesic effect for 6 to 8 hours, so appropriate dosing for pain is every 6 to 8 hours as opposed to the once-daily dosing used for maintenance.

Methadone

Methadone has both opioid and nonopioid actions. Nonopioid actions include inhibition of the reuptake of monoamines (eg, serotonin, norepinephrine) and inhibition of N -methyl- d -aspartate (NMDA) receptor, pharmacologic actions that result in additional analgesia. Activation of the NMDA receptor can produce central sensitization (ie, lowering central nervous system pain thresholds); blocking this receptor may help mitigate the development of hyperalgesia and tolerance. NMDA receptor antagonism may also be helpful in treatment of neuropathic pain states. Methadone has gained popularity as an analgesic for this purpose. It can be particularly helpful as an analgesic for burn patients who have developed tolerance and or hyperalgesia as a results of prolonged opioid exposure.

It should be cautioned that methadone possesses idiosyncrasies that can make its use by inexperienced prescribers dangerous. Methadone is unique in that it has a variable terminal half-life that ranges between 7 and 65 hours. In other words, it will not reach steady state for several days after initiation or dosage adjustments. Too rapid or aggressive dose escalations can lead to drug accumulation and respiratory depression. Fortunately, renal and hepatic dysfunction is not known to cause methadone accumulation.

Methadone also has the ability to prolong the QT interval. Though the dose at which this is most likely to occur is still not agreed on, it is well accepted that this is an unlikely occurrence at doses below 100 mg per day. QT prolongation, however, can be more common in critically ill patients who may also necessitate life-saving medications known to prolong the QT interval, such as antimicrobials and antiarrhythmics, in the setting of frequent electrolyte disturbances.

Continuous methadone infusions and enteral methadone have been described to provide analgesia in critically injured burn patients and to help with weaning high-dose opioids and facilitate discontinuation of mechanical ventilation.

Acetaminophen

Acetaminophen in a well-known analgesic with a mechanism of action that has yet to be defined. Studies suggest that there may be involvement of multiple receptor types, including cannabinoid receptors, and also inhibition of prostaglandin synthesis. Clinical studies in surgical patients show improvement in pain and lowered opioid consumption with acetaminophen use. There is a ceiling effect with respect to analgesia and acetaminophen by itself is rarely appropriate for the treatment of burn pain in an acute inpatient setting. It is best used in combination with other adjuncts.

Nonsteroidal Anti-inflammatory Drugs

Like acetaminophen, nonsteroidal anti-inflammatory drugs are widely used analgesics. They are potent anti-inflammatory medications with mechanism of action that this is generally thought to be through inhibition of the enzymes that synthesize prostaglandin. However, a variety of other peripheral and central mechanisms are also emerging that is beyond the scope of this article. Their utilization for patients with acute burn injury is limited by side effects such as gastric ulceration and renal insufficiency. Their use can reduce the amount of opioid needed by up to 20% to 30% because these drugs act synergistically with opioids.

Antidepressants

Antidepressant medications are gaining recognition for their role as part of a multimodal treatment in chronic pain. The class of antidepressants most recognized for their analgesic properties in neuropathic chronic pain states are the tricyclic antidepressants (TCAs) and the combined serotonin and norepinephrine reuptake inhibitors (SNRIs). Of the TCAs, amitriptyline and nortriptyline are agents more frequently used for pain. The SNRIs include duloxetine, milnacipran, and venlafaxine. Like the SNRIs, the TCAs block reuptake of serotonin and norepinephrine.

The analgesic effect of antidepressants does not correlate with the treatment of depression. In fact, for the TCAs the analgesic benefit occurs before the anticipated effect on mood (about 2 weeks for pain vs 6–8 weeks for mood). It should be stressed that antidepressants cannot be used for acute control of pain because their dose may be need to be titrated and adjusted slowly to minimize side effects. Further, the doses used for analgesia are typically lower than those used for the treatment of a mood disorder and serum levels do not correlate with degree of analgesia.

The analgesic action of these medications is thought to occur at the level of the spinal cord through bulbospinal pathway, which is a descending inhibitory pathway that modulates dorsal horn function. By blocking uptake of serotonin and norepinephrine, TCAs and SNRIs increase the activity of descending inhibitory pathways. There is probably also a supraspinal pathway mode of action, but this has yet to be determined.

These medications have not formally been studied in pain related to burn injury. Their use in burns is extrapolated from experience with treating chronic pain disorders. With respect to pain disorders, antidepressants are most widely used to neuropathic pain, such as with peripheral neuropathy, and centralized pain states, such as in fibromyalgia. Because acute burn pain often becomes long-lasting and can remain severe, it can take on neuropathic features with elements of central sensitization. Furthermore, neuropathy is commonly also seen in later stages of burn injury as dysesthesias and itching. Antidepressants can also be used for their opioid-sparing effect.

Common side effects of TCAs are largely due to antimuscarinic and antihistaminic effects. These include dry mouth, urinary retention, constipation, and sedation. SNRIs, which are newer than TCAs, are thought to have fewer associated side effects.

Antiepileptics

Antiepileptic medications are increasingly used to treat neuropathic pain states. In burn injury, in which there is a widespread damage to cutaneous nociceptors, many patients experience pain that is described as pins and needles, or itching, in addition to burning. These pain descriptors are hallmarks of neuropathic pain states. Furthermore, with a large injury and pain that is present for a substantial length of time, there is potential for central sensitization, further making the case that burn injury has a neuropathic component.

The gabapentinoids, pregabalin, and gabapentin have been studied in burn patients. Gabapentin has been shown to reduce pain scores, decrease opioid consumption, and decrease the burning pain. Similarly, pregabalin has been shown to be helpful in reducing the unpleasantness of pain, as well as procedural pain.

Other antiepileptics used in pain management include topiramate, oxcarbazepine, and carbamazepine. However, there are few data on their use in burn injury. Side effects of these medications include electrolyte disturbance with topiramate and oxcarbazepine, and aplastic anemia and Stevens-Johnson syndrome with carbamazepine.

Ketamine

Ketamine is a potent analgesic that is an NMDA receptor antagonist. Its hallmark property is the ability to produce a dissociative state when used at anesthetic doses (see later discussion).