Narcotics are the mainstay analgesics to control pain in the intensive care settings. However, patients frequently require escalating doses of narcotics for pain control leading to higher risks of side effects and complications [
This interventional double-blind randomized clinical trial (RCT) was conducted between January 2011 and January 2015 at King Abdulaziz Medical City (KAMC), Riyadh, KSA, a 1500-bed medical university hospital. The PICU is a multidisciplinary unit admitting about 900 patients per year under 14 years of age. It was conducted observing the principles of Helsinki declaration. This study was approved by the Institutional Review Board and King Abdullah International Medical and Research Center (KAIMRC) and involved pediatric intensive care unit patients (2–14 years). This study is registered with clinicaltrials.gov (identifier:
The primary outcome in this study was the cumulative dose of fentanyl in subjects with intervention of either dextromethorphan or placebo.
Upon admission all the patients were assessed for eligibility to be enrolled in the study as per inclusion and exclusion criteria. Inclusion criteria were as follows: (1) patients admitted in PICU within 72 hours of admission and (2) patients receiving intravenous infusion of fentanyl. The exclusion criteria were as follows: (1) patients who are less than 2 years of age, (2) patients who are hemodynamically instable, (3) enteral route which was contraindicated for medication administration, and (4) patients with hepatic or renal failure/dysfunction or multiorgan failure. Verbal and written information was provided to eligible patients/parent(s)/guardian(s). Informed consent was obtained once they decided to participate. Subjects’ biodata and consent were entered in hospital electronic order system for randomization. Sample size was calculated on the basis of an absolute enhanced effect of 75–100% and assuming 10% drop out rate our estimated sample size was total number of 36 to give study a power of 80%. 36 randomization numbers were allocated to two groups by random chance and each group received 18.
Subjects, parent(s)/guardian(s)/caregiver, investigators, pharmacists, nurses, and paramedics were kept blinded. The intervention in this study was administration of dextromethorphan via nasogastric or orogastric tube. The unblinded research pharmacist from KAIMRC prepared placebo medicine that was identical to dextromethorphan in physical properties.
Intervention study medicine was administered every 8 hours through nasogastric or orogastric tube in the standard recommended doses of 0.3 mg per kilogram per dose by bedside nurse.
The total duration of intervention was 96 hours. During this time frame, we had criteria to remove subjects from study if one or more of the following circumstances arise: (a) if the narcotic infusion was discontinued, (b) if subject developed hemodynamic instability, (c) withdrawal request by parent(s)/guardian(s), and (d) if subject’s Glasgow Coma Scale (GCS) fell below 5 or subject was declared dead.
Enrolled subjects were continuously monitored with PICU monitoring system and pain was assessed via FLACC (face, legs, activity, cry, and consolability) and/or faces scales by the staff who were well trained and experienced with the universally standard goal of achieving pain control with minimum dose of fentanyl [
We searched literature in PubMed with mesh headings of analgesia, acute care, narcotics, fentanyl, morphine, adjunctive therapies, NMDA antagonists, and dextromethorphan.
We recorded the data on Microsoft Excel, version 2007. The data were then exported to IBM Statistical Package for Social Sciences Statistics, version 20 (IBM Inc., Armonk, New York, USA), for further analysis by intention to treat. Demographic variables were assessed using Kolmogorov-Smirnov test for distribution and reported as median with interquartile ranges (IQR) and groups were compared using Mann–Whitney test. Biochemical data and fentanyl doses group comparison are presented as means with standard deviation (SD) and groups were compared using Student’s
Figure
Flow diagram.
In Tables
Demographic characteristics. Clinical Outcomes of subjects in Groups 1 and 2 in RCT. Kolmogorov-Smirnov test used to assess distribution. nc, not computed.
Characteristics | Group 1: dextromethorphan (number = 16) | Group 2: placebo (number = 13) |
|
---|---|---|---|
Median (IQR) | Median (IQR) | ||
Age (Yr.) | 9.7 (8–12) | 5.54 (3.5–6) | 0.0015 |
Gender: Male (number) | 9 | 10 | nc |
LOS-PICU (days) | 9 (6–21) | 12 (6–24) | 0.431 |
LOS-Hospital (days) | 16.5 (9–46) | 24.5 (12–61.5) | 0.501 |
PRISM | 17 (15–21) | 18.1 (15.5–22) | 0.75 |
Intubated (number) | 16 | 13 | nc |
Underlying diagnosis (number) | |||
Trauma | 10 | 10 | 0.57 |
Hem/onco | 3 | 0 | NA |
Post-op | 2 | 1 | 0.672 |
Respiratory failure | 1 | 1 | 0.879 |
Burn | 0 | 1 | NA |
Fentanyl infusion-start |
2 (1–4) | 2 (1–3) | 0.16 |
Fentanyl infusion-end |
3 (2–4) | 3 (1–4) | 0.7 |
Midazolam infusion-start mg/kg/hr | 0.09 | 0.11 | 0.36 |
Midazolam infusion-end mg/kg/hr | 0.16 | 0.18 | 0.27 |
Biochemical variables of subjects in groups 1 and 2 in RCT. Groups compared via Student’s
Group 1: dextromethorphan (number: 16) | Group 2: placebo (number: 13) |
| ||||
---|---|---|---|---|---|---|
Mean |
|
Mean |
|
|||
WBC (×103/mm3) | Start | 12.81 | 6.337 | 14.92 | 5.937 | 0.673 |
End | 11.13 | 3.879 | 11.31 | 3.225 | 0.894 | |
Hemoglobin (g/L) | Start | 103.56 | 16.252 | 112.23 | 12.544 | 0.104 |
End | 97.81 | 12.079 | 101.92 | 12.493 | 0.3747 | |
Platelets (×103/mm) | Start | 302.31 | 169.591 | 362.54 | 166.289 | 0.348 |
End | 287.06 | 138.546 | 352.00 | 144.741 | 0.228 | |
Aspartate transaminase (AST) (units/L) | Start | 44.25 | 14.040 | 42.23 | 12.357 | 0.687 |
End | 57.80 | 32.182 | 52.60 | 13.390 | 0.747 | |
Alanine transaminase (ALT) (units/L) | Start | 46.80 | 11.351 | 42.13 | 12.426 | 0.404 |
End | 48.80 | 18.431 | 45.33 | 21.068 | 0.777 | |
Prothrombin time (seconds) | Start | 10.29 | 1.816 | 9.77 | 1.964 | 0.419 |
End | 11.63 | 1.598 | 10.90 | 1.969 | 0.433 | |
International normalized ratio | Start | 1.00 | 0.000 | 1.08 | 0.277 | 0.289 |
End | 1.00 | 0.000 | 1.00 | 0.000 | 1 | |
Activated partial thromboplastin time (seconds) | Start | 27.29 | 5.525 | 27.08 | 5.795 | 0.918 |
End | 26.38 | 4.104 | 29.10 | 6.226 | 0.302 | |
Serum sodium (mmol/L) | Start | 138.81 | 4.969 | 139.77 | 3.632 | 0.591 |
End | 140.94 | 6.698 | 142.38 | 5.268 | 0.545 | |
Serum potassium (mmol/L) | Start | 3.88 | 0.500 | 3.85 | 0.555 | 0.879 |
End | 3.94 | 0.574 | 3.69 | 0.630 | 0.377 | |
Serum chloride (mmol/L) | Start | 110.50 | 7.294 | 106.77 | 6.126 | 0.157 |
End | 107.75 | 8.560 | 106.46 | 4.630 | 0.651 | |
CO2 (mmol/L) | Start | 20.36 | 4.396 | 19.36 | 7.953 | 0.693 |
End | 25.00 | 3.211 | 25.73 | 3.901 | 0.611 | |
Blood glucose (mmol/L) | Start | 6.67 | 1.676 | 8.58 | 4.100 | 0.18 |
End | 6.73 | 1.870 | 6.90 | 3.178 | 0.868 | |
Blood urea nitrogen (mmol/L) | Start | 2.50 | 1.211 | 3.54 | 1.391 | 0.048 |
End | 2.63 | 1.962 | 1.69 | 0.751 | 0.12 | |
Serum creatinine ( |
Start | 32.25 | 11.947 | 37.15 | 7.069 | 0.208 |
End | 30.00 | 14.367 | 36.38 | 10.524 | 0.193 |
In Table
Primary outcome in RCT. Comparison of dose(s) of fentanyl in groups. Groups compared via Student’s
Dose(s) | Group 1: dextromethorphan |
Group 2: placebo |
|
---|---|---|---|
Cumulative | |||
Mean | 217.94 | 268 | 0.127 |
Std Dev | 87.7 | 81.84 | |
SEM | 21.9 | 22.7 | |
Infusion | |||
Mean | 215.63 | 256.69 | 0.257 |
Std Dev | 89.27 | 101.6 | |
SEM | 22.32 | 28.2 | |
PRN | |||
Mean | 2.31 | 3.62 | 0.101 |
Std Dev | 2.21 | 1.85 | |
SEM | 0.55 | 0.51 |
Variability of fentanyl dose requirements in subjects with different weight percentiles in dextromethorphan group.
Multiple therapies had been mentioned in the literature which are considered adjunctive to narcotics. Some of these are beneficial to patients who have chronic pain such as antidepressants and anticonvulsant and some are beneficial to patients with acute pain such as acetaminophen and ibuprofen [
Dextromethorphan (DM) is an antitussive drug. It is one of the active ingredients used to prevent coughs in many over-the-counter cold and cough medicines. DM is the D-isomer of the codeine analog of levorphanol but has little analgesic or addictive properties. However, it does act on the cough center in the medulla oblongata by elevating the threshold for coughing. In usual doses, the drug can cause dilation of pupils, but without significant reduction of respiratory rate. Dextromethorphan may cause slight elevations in blood pressure [
Dextromethorphan (DM) may play an important role in conditions of glutamate excitotoxicity (i.e., amyotrophic lateral sclerosis) because of its ability to suppress the overactivity of the glutamate system in the CNS [
The researchers have explored the role of dextromethorphan as adjunct to narcotics pain control in acute setting. Elliott et al. performed an animal study and showed that dextromethorphan decreased the tolerance to analgesic effect of morphine [
Our study has multiple limitations. Most notably it is single-centered, a possible effect on external validity. Despite efforts some cofounding factors might had been overlooked. Administration of dextromethorphan through nasogastric route and not intravenously may have an impact on our study results. In conclusion, this study did not detect any adjunctive effect of dextromethorphan when added to fentanyl for control of acute pain in children admitted with acute critical care illness in PICU.
In the future, we suggest a randomized controlled trial using higher doses of dextromethorphan preferably administered intravenously. We also suggest evaluating dextromethorphan’s role in subset of particular patients having existing chronic pain due to underlying conditions such as patients with oncologic problems who get admitted in PICU for acute critical care illness.
Dextromethorphan
Pediatric intensive care unit
N-Methyl-D-aspartate.
The authors have no commercial associations or sources of support that might pose a conflict of interests.
All authors have made substantive contributions to the study, and all authors endorse the data and conclusions.
The authors acknowledge King Abdullah International Medical Research Center.