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12 Articles in Volume 16, Issue #10
2016 Practical Clinical Advances: Ketamine and Metformin
Case Challenge: Amniotic Allograft Reduces Joint and Soft Tissue Pain
Challenges of Treating Young Patients With a Terminal Prognosis
Defining Palliative Care
Discussing Benefits of Palliative Care
Evaluation of Antiemetic Pharmacotherapy in the Setting of Opioid Withdrawal
Fibromyalgia, Chronic Fatigue, and Chronic Fatigue Syndrome
Gabapentin Dosing for Neuropathic Pain
IV Acetaminophen Reduces Need for Opioids in Burn Patients
Opioid-Induced Constipation: New and Emerging Therapies—Update 2016
Osteopathic Treatment Considerations For Head, Neck, and Facial Pain
Tips From the Field: Deconstructing the Art of Headache Medicine

IV Acetaminophen Reduces Need for Opioids in Burn Patients

Small study finds IV acetaminophen could be included in the initial and perioperative pain control protocol of burn patients based on its analgesic effect, safety profile, stable pharmacodynamics, limited adverse events, and easy accessibility.

Inadequate pain management of burn patients can lead to post-traumatic stress disorder, depression, and other psychiatric disorders.

Poor pain management of burn patients has long-lasting effects, even after the burn itself is healed. Several studies have established an association between inadequate burn pain control and subsequent development of psychiatric disorders, such as post-traumatic stress disorder, delirium, maladaptive behaviors, and depression.1,2 In addition, poorly managed pain, combined with a catabolic state in burn patients, contributes to immune system impairment, which increases the risk of infection.

The pain associated with burns, which involves both nociceptive and mechanical pain pathways, is one of the most challenging forms of acute pain to treat. The tissue damage secondary to burns causes intense activation of nociceptors via chemical mediators, and the surgical protocol for burn injuries usually worsens the severity of the pain due to secondary mechanical injury. Finally, the cycle of compounding pain in itself will restrict and interfere with the patient’s ability to participate in physical therapy and functional restoration, increasing the length of the hospital stay and, thus, promoting further complications.

A multimodal pain management approach is warranted, and medication selection may vary according to the extent of injury and system involvement. Traditionally, opioids are the first line in the analgesic management algorithm of burn pain, and due to the severity of the pain, patients commonly will use larger than usual doses and, thus, will have more pronounced adverse events (AEs).

The aim of this prospective study was to determine the role of intravenous (IV) acetaminophen in reducing the amount of opioids burn patients require.

Study Methods

After institutional review board (IRB) approval, all patients admitted to the burn service were selected for participation in this study. Written consents were obtained.

The inclusion criteria consisted of voluntary participation, with patients older than age 18 and younger than 75 included. In addition, to be included patients had to have avoided nonsteroidal anti-inflammatory drug (NSAID)- or acetaminophen-containing products the day of the surgery, had to have an American Society of Anesthesiologist (ASA) health status of 1 or 2, and had to have an injury involving less than 20% of their body surface area (BSA) from any type of burn.

Between May 2013 and May 2016, patients admitted to the burn intensive care unit, burn service step-down unit, and surgical floor were surveyed. The patients were then assigned to receive 1 of 2 pharmacologic treatments after a burn-related surgery: the intervention group received 4 doses of 1,000 mg of IV acetaminophen plus IV opioids (morphine or hydromorphone) and patient-controlled analgesia (PCA); the control group received PCA morphine or hydromorphone.

The surgical procedure performed in all patients was a split thickness skin graft (STSG) that consisted of debridement of the epidermis of the affected area followed by a repair with an autologous skin graft, usually collected from the thigh.

The medication administration protocol for the intervention group involved an initial dose of 1,000 mg IV acetaminophen prior to surgical incision, with subsequent administration every 6 hours for a total of 4 doses over 24 hours.  

Opioid administration to both groups was performed via PCA for at least 24 hours. It was discontinued only after the patients were able to tolerate oral medications and their pain was controlled with these medications. The total use of opioids for 24 hours was recorded.

We surveyed the patients’ pain control with a questionnaire that included a numerical scale assessing pain at preoperative, immediate postoperative, overnight, and interview time points. Additionally, we used a 1- to 5-point scale, with 1 point signifying complete dissatisfaction and 5 points signifying complete satisfaction with the pain control methods used. Finally, we added 2 questions and used the same 1- to 5-point scale to assess the patients’ knowledge of AEs and whether pain control was the patients’ main priority.

The study’s primary objective was to establish whether there was any difference in opioid consumption between the 2 study groups, expressed in IV morphine equivalents (IVMEs). Secondary objectives included the evaluation of any difference in pain scores between the groups, reduction in the baseline pain score, the total amount of opioid used, and patient satisfaction with the pain control measures.

For the primary objective, we used independent t-tests to compare the groups with respect to pain scores and morphine-equivalent consumption.

Study Results

A total of 61 patients met our inclusion criteria. The patients’ mean age was 43.3 years, and there was no age difference between the 2 groups.  

Out of 29 patients in the intervention group, all received 1 IV acetaminophen dose (1,000 mg) during the procedure, but only 25 (86%) received the complete protocol of 4 doses (4,000 mg). Of the 4 patients who did not complete the whole IV protocol, 2 received 2 doses (2,000 mg), were managed with PCA opioids, and were dropped from the study. The remaining 2 patients were dropped due to the use of spinal anesthesia during the procedure.

Of the 32 control patients, 9 were dropped from the study: 2 patients due to the use of spinal anesthesia, 2 received IV NSAIDs or oral hydrocodone in the recovery unit, 3 did not get a PCA, and 2 were discharged home the same day.

Based on the patients who were eligible and completed the survey, the average rating of preoperative pain score was 6.72 in the intervention group and 6.13 in the control group (P=0.37). The average postoperative pain rates were 7.04 and 7.34, respectively (P<0.78), whereas the overnight score rating was 4.8 in the intervention group compared with 5.56 in the control group (P<0.34). Finally, pain scores at the time of the interview were 4.6 and 4.73, respectively (P<0.48). These results indicate that there was no statistical difference in pain scores between the 2 groups.

The 24-hour PCA usage was monitored after the arrival to the recovery unit. The morphine PCA settings were standardized to 1 mg every 8 minutes with an 8 mg/hour limit. The hydromorphone settings were left to provider preference, and the total dose conversion of hydromorphone to morphine was 7:1; both groups had similar numbers of hydromorphone users.  

When comparing the total amount of opioids used, the average amount of IVMEs was 35.6 mg in the intervention group vs 52.3 mg in the control group (Figure 1). There was a statistically significant difference between the control and intervention groups, showing 30% more opioid consumption in the control group (P<0.041).

In regard to patient satisfaction with the method used, the majority of the control group (75%) was completely satisfied with the method used, and the remaining patients (25%) were mostly satisfied. In the intervention group, only half (52%) were completely satisfied with the method used, 32% were mostly satisfied, and 16% were partially satisfied.

Discussion

The site of action of the analgesic effect of acetaminophen is thought to be the central nervous system (CNS). Although the precise mechanisms of action of this central effect are not known, there are several theories, including a cannabinoid receptor agonist, serotoergic bulbospinal pathways, cyclo-oxygenase-3 isoenzyme inhibition, and a transient receptor potential cation channel subfamily V member 1 (TRPV-1) agonist-mediating response to pain.3,4 The antipyretic effect is thought to be mediated by the inhibition of prostaglandin synthesis within the hypothalamus.5

The pharmacokinetics of IV acetaminophen have been described in several studies, and the serum therapeutic level required to produce an analgesic effect is 16 mcg/mL in adults and 10 mcg/mL in children.6 IV infusion of 1,000 mg of acetaminophen produces a rapid elevation in plasma concentrations and higher peak levels compared with oral acetaminophen.5

In a study involving 8 doses every 6 hours in healthy volunteers, these pharmacokinetic differences continued with repeated doses.7,8 With the use of IV acetaminophen, a clinical analgesic effect occurs within 15 minutes of administration, with a peak effect within 1 hour and a duration of effect of 4 to 6 hours. The pharmacokinetics have been compared to oral and rectal doses of acetaminophen.7 The mean peak concentration after infusion of IV acetaminophen is 70% higher than the mean peak concentration seen with an equivalent oral dose. The median time to reach maximum plasma concentration (Tmax) is 15 minutes for IV acetaminophen, compared with 45 to 75 minutes for oral acetaminophen and 3 to 4 hours for rectal administration.  

With the high plasma concentration, acetaminophen readily diffuses across the blood-brain barrier, with rapid and high levels in the cerebrospinal fluid.8,9 There are significant differences between IV, oral, and rectal acetaminophen in the peak and total amount of the drug in the cerebrospinal fluid.10 The half-life of IV acetaminophen in the cerebrospinal fluid is 3.2 hours.11

The AE profile of IV acetaminophen is widely documented, and the drug is known to have a very good safety record, making it an ideal drug to be used in patients at risk for the deleterious opioid or NSAID effects. The main concern with regard to acetaminophen (although rare) is its potential to cause hepatotoxicity. A case report by Lee et al documented an IV acetaminophen–induced hepatotoxicity. Although the patient received the manufacturer’s recommended dosing of IV acetaminophen, she accumulated an acetaminophen level of 34 mcg/mL and developed elevated liver enzymes.6

Since the approval of IV acetaminophen use in the United States, numerous studies have been launched to determine its efficacy in treating mild to moderate pain and as an adjunct in multimodal pain management.11-14 However, different studies have shown conflicting results.

Some of this conflict can be explained by the type of pain being managed, given that IV acetaminophen is more efficacious in managing somatic pain. There is sufficient literature on the use of acetaminophen for pain related to orthopedic, bariatric, gynecologic, lumbar, and laparoscopic surgeries,11-12 but only case reports on burn pain were found. As mentioned earlier, burn pain is difficult to control. Opioids, as the first line in pain management, are associated with an extensive AE profile (respiratory depression, constipation, dizziness, delirium, ileus, etc).13

In an extensive review of 16 randomized control trials by Macario et al, IV acetaminophen was found to be comparative to the analgesic efficacy of NSAIDS (IV parecoxib, metamizol) and oral ibuprofen.14 Overall, 12 of 14 placebo-controlled studies found that patients receiving IV acetaminophen had improved analgesia, and 7 of the 8 studies showed similar analgesic outcomes.14

In addition to the multimodal approach to pain management, the concept of pre-emptive analgesia also has been studied. The mechanism behind this theory involves preventing peripheral and central sensitization of the CNS, thereby reducing the overall pain perception. Doleman et al reviewed somatic pain studies comparing pre-emptive acetaminophen with post-incision acetaminophen.15 The results of this review demonstrated that pre-emptive acetaminophen resulted in lower postoperative pain scores up to 2 hours postoperatively; however, the clinical effect is small. In addition, a moderate, clinically significant reduction in 24-hour opioid consumption was observed, with a delayed time to first analgesic request and a reduction in the incidence of postoperative vomiting.

Despite this early analgesic effect, pre-emptive acetaminophen did not reduce pain scores beyond the immediate postoperative period or reduce any other opioid-related AEs, although it is possible these studies were underpowered for these outcomes.15

Benefit also has been seen in orthopedic surgeries, according to Singla et al, who investigated the efficacy of a single dose of IV acetaminophen for postoperative pain after hip arthroplasty.8 This study demonstrated that in nearly all primary and secondary end points, there were statistically significant differences with improved analgesia, rapid onset of action, and opioid consumption decreases of more than 50% when compared with placebo.8

Conversely, conflicting results have been seen in numerous other studies on the use of IV acetaminophen in postoperative pain control. For example, in cardiac surgery, the management of postoperative pain remains clinically challenging.16,17 A systematic review of IV acetaminophen after adult cardiac surgery by Douzjian et al found that compared to ketorolac and tramadol, pain control was significantly less effective with IV propacetamol, based on a 5-item verbal pain score.16 A significantly greater number of patients in the IV propacetamol group reported persistent “severe pain” after surgery compared to the 2 other analgesic groups (P<0.05). Finally, patients in the IV propacetamol group more often required a second analgesic dose. The authors concluded that propacetamol was the least effective analgesic.

Another study showed that IV acetaminophen is not effective after laparoscopic surgeries. Strode et al compared IV acetaminophen to placebo for pain management after laparoscopic sleeve gastrectomy and observed that the pain score was significantly decreased compared with baseline at 12, 16, and 20 hours after surgery in the acetaminophen-treated patients but not in the placebo group. However, total narcotic use, time to rescue of first narcotic dose, and total PACU narcotic dose were not statistically different between the 2 groups.18

A similar study by Wang et al investigating the effect of IV acetaminophen on postoperative opioid use in bariatric surgery patients did not yield beneficial results. The review analysis indicated that IV acetaminophen was ineffective in reducing opioid consumption in bariatric surgery patients. In fact, the opioid consumption was significantly higher in IV acetaminophen-treated patients than in untreated patients.19

The role of acetaminophen in neuropathic pain has not been elucidated.

Conclusion

In this prospective randomized control study, we investigated the potential benefits of IV acetaminophen in reducing opioid consumption in burn pain patients, as well as examined AEs associated with it. Our findings are consistent with the evidence thus far available.

Patients who have suffered an acute somatic injury and are being exposed to further injury during burn debridement are found to benefit from pre-emptive IV acetaminophen. This was demonstrated by a significant decrease (30%) in opioid consumption. Conversely—perhaps due to the lack of sedative, and possibly euphoric, AEs usually associated with opioids—the intervention pain control satisfaction scores make this medication seem less effective than opioids alone.

In addition, we believe that both groups consumed a lower amount of opioids, given that all participants were educated about the AEs frequently seen with opioid use (eg, nausea, emesis, pruritus, constipation, and potential addiction) prior to signing the consent. Furthermore, the intervention group also was informed of the AEs of IV acetaminophen (nausea, headache, insomnia), which in comparison to the opioid AEs seem to be less detrimental.

Weaknesses in the current study include the lack of power and the small percentage of body surface injured; it may not apply as a guideline in patients who may have larger burns and/or more severe multiorgan involvement. However, the current study serves as a first step that warrants further study of the utility of acetaminophen in these sicker populations.  

In conclusion, IV acetaminophen could be included in the initial and perioperative pain control algorithm of burn patients based on its analgesic effect, safety profile, stable pharmacodynamics, limited AEs, and easy accessibility.

Last updated on: December 12, 2016
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Evaluation of Antiemetic Pharmacotherapy in the Setting of Opioid Withdrawal

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