3.2.2 Toxicities
In the ketamine group, two children (9.1%) complained of adverse
events. This included one child with vomiting and another child who
complained of vertigo. In the placebo group, five children (22.7%) had
an adverse event, including three children with vomiting, one with
nausea, and one with pain in the abdomen. All the adverse events noted
in the two groups were transient and mild. The difference between the
occurrence rates of adverse events in the two groups was not
statistically significant (p=0.412) (Table 2).
DISCUSSION
This study demonstrated no significant efficacy of ketamine mouthwash
(at a dose of 1 mg/kg) for OM pain reduction in children, both in terms
of clinical significance (but there was an extra pain reduction of 0.32
points on a 6-point scale as compared to placebo) as well as statistical
significance (p=0.425). A similar inference was suggested from the
observation that there was no significant reduction in the requirement
of rescue analgesic medications in the ketamine group as compared to
placebo in the study. Ketamine mouthwash at 1mg/kg was safe, with only
two children experiencing adverse events, both of which were mild and
transient.
All the studies of ketamine mouthwash in severe oral mucositis pain in
cancer patients have been provided in Table 3. There are noticeable
differences in the patient profile and the study design in the previous
studies as compared to the current study. A pain reduction of 1.64
points on the 6-point scale in the current study was comparable to the
pain reduction of 2 points on a 10-point scale at 1-hour of drug
administration in the study carried out by Shillingburg A et
al13, but it carries little significance as the
placebo arm also demonstrating a pain reduction of 1.32 points on the
6-point scale in the current study.
There can be several possible reasons for the lack of significant pain
reduction in the current study: (1) the most straightforward explanation
is that ketamine mouthwash is truly ineffective for OM pain, as was
statistically demonstrated by the current study. The underlying reason
for this could be pharmacodynamic, in the sense that the local receptors
in oral mucosa for ketamine action may not be adequate in number or
function. However, ketamine gargles have been shown to significantly
reduce postoperative sore throat, suggesting that there are indeed
receptors for ketamine action in the oral mucosa.18The effect of mucosal inflammation and ulceration on such receptors is
not precisely known, especially in children, and requires further
research. (2) Another possible explanation could be that the dose of
ketamine used in the study, i.e., 1 mg/kg (maximum 40 mg), was
inadequate. Determining an appropriate dose for the study was difficult
considering that all previous studies on ketamine mouthwash for OM was
done in adults (all of which used a dose of 20 mg/dose of ketamine
mouthwash). An arbitrary dose of 1 mg/kg/dose was chosen for this study.
This dose was tried on three children with severe OM before starting the
study; all three children reported some pain relief. However,
considering the lack of efficacy of ketamine shown by this study, it
might be imperative to test a higher dose of ketamine mouthwash for OM
before its benefit can be conclusively ruled out. (3) The third
possibility is remote that the enrolled children were not able to
appropriately understand and express their pain scores since the
enrolled children were relatively older (8-18 years), and the pain scale
used was a commonly employed and validated scale for children. (4)
Similarly, periodic assessment of the drug formulation was done and drug
adequately stored, thus eliminating the likelihood of the drug
formulation being ineffective.
A major strength of this study was the design of a randomized,
placebo-controlled trial. The masking and allocation concealment were
ensured stringently in the study. A validated pain scale was used, which
could be easily comprehended by the children. Supervised administration
of the drug was done. There were no protocol violations and intention to
treat analysis in the study.Limitation: This was a single-institute study (two centers).
Although the enrolled children exhibited a variety of cancer profiles,
the racial profile was similar for all children. The study required the
administration of only a single dose ketamine mouthwash with a short
follow up period. This was done keeping in mind that this was the first
documented instance of the use of ketamine mouthwash in children with
cancer, and the safety profile of the drug over long term use was not
definitively known. The primary outcome for our study was decided as a
reduction in pain score and not the reduction in the use of systemic
analgesics, even though the underlying premise for the study was
arguable to find a safe topical agent so that the adverse effects of the
systemic analgesic drugs could be minimized. However, the overall
requirement of systemic analgesics was less, as seen in the study’s
placebo arm, and it was much more challenging to demonstrate a
statistical significance.
In conclusion, ketamine mouthwash at a dose of 1 mg/kg did not
significantly reduce chemotherapy-induced severe oral mucositis pain in
children, and it did not decrease the need for rescue pain medication.
Further research is needed with a higher dose of ketamine before a
definite conclusion can be drawn regarding the efficacy of ketamine
mouthwash in children with oral mucositis pain in children with cancer.