4.3 Topical ketamine
The evaluation of topical ketamine preparations for chemotherapy-induced
peripheral neuropathic pain has yielded variable results, with some
suggesting a promising role but many studies indicating no significant
benefit.91,92,93 Topical ketamine is a safe and
effective analgesic for decreasing post-tonsillectomy pain in children,
and has been used as a skin preparation for non-cancer
pain.26,94,95 Preliminary evidence for ketamine
mouthwash for oral mucositis pain had suggested a beneficial role in
adults, but a recent RCT evaluating the role of ketamine mouthwash for
oral mucositis pain relief in children (N=44; 8-18 years) found ketamine
to be ineffective at a dose of 1 mg/kg.96,97,98,99 The
summary of various studies of ketamine mouthwash in oral mucositis (OM)
pain in cancer patients has been provided in Table 4.
There are several potential advantages of using topical agents over
systemic, such as higher analgesic concentration at the site of pain,
faster onset of action, low or no systemic drug levels and side effects,
decreased risk of drug interactions, better drug compliance, and
decreased risk of abuse or dependence.100 Considering
these benefits and the fact the patients with cancer are already on a
concoction of systemic agents, discovering effective topical agents
could prove to be very useful in this group in providing desired
therapeutic effects while minimizing adverse effects and harmful drug
interactions. Hence, further studies investigating the topical delivery
of ketamine for analgesic and anti-inflammatory effects are the need of
the hour.
Adverse effects
Commonly seen adverse effects include sedation, nausea, vomiting,
hallucinations, anorexia, urinary retention, hypertension, tachycardia,
muscle stiffness, increased respiratory secretions, vertigo, and
ataxia.101,102 Nystagmus, diplopia, laryngospasm,
reversible cystitis, and central diabetes insipidus have been noted on
rare occasions.103,104 Abrupt discontinuation of
ketamine infusion may lead to anxiety, tremors, sweating, and emergence
reactions.105 These reactions manifest as
hallucinations, vivid dreams, and delirium. There is also evidence to
believe that the emergence reactions are seen less commonly in children
as compared to adults.106,107 As noted previously, the
notorious psychomimetic effects of ketamine have been seen to be much
less frequent at analgesic doses. The emergence of reactions can be
minimized by concomitantly using a benzodiazepine with
ketamine.108 All the aforementioned adverse effects
are rare with topical preparations.96,97,98,99
The conventional contra-indications to the use of ketamine include
conditions in which a sudden increase in systemic blood pressure might
be dangerous (cerebrovascular accidents, myocardial infarction, aortic
dissection, aneurysm), known or suspected schizophrenia spectrum
disorder and documented hypersensitivity. The American College of
Emergency Physicians has also listed age less than three months as an
absolute contraindication to the use of ketamine, due to a high risk of
airway complications, although ketamine is still occasionally used in
this age group.101 Ketamine is to be avoided in
patients with glaucoma due to its propensity to cause intraocular
pressure. A few other relative contraindications include a history of
airway instability, known cardiovascular disease, porphyrias, and
hyperthyroidism (increased sympathomimetic activity). Additionally, in
the absence of sufficient safety data available for ketamine levels in
breastmilk, it is recommended that alternate agents be preferred when
feasible.109
Early reports about ketamine dating as far back as the 1970s suggested a
propensity of ketamine to cause intracranial
hypertension.110,111 However, since then ample
evidence has questioned this notion. Ketamine has been shown not to
cause intracranial hypertension in patients, including in those with
traumatic brain injury in children.112,113,114 In
fact, ketamine by maintaining cerebral perfusion pressure may have a
neuroprotective effect, especially under conditions of controlled
ventilation.
Concerns in children
Long term use of high dose ketamine has been linked to adverse
neurodevelopmental outcomes, including those related to memory,
cognition and executive function.115 However, most of
such information has been derived from studies done on recreational
abusers of ketamine and is unlikely to have much basis in the clinical
use of controlled doses of ketamine. Nevertheless, the abuse potential
of ketamine is well-documented and has to be kept in mind. Moreover,
even sub-anesthetic doses of ketamine have been shown to cause some
impairment in memory and attention.116 It is therefore
imperative for clinicians to monitor for any such effects during the
administration of ketamine to children.
In the developing brain of some animal models, ketamine has been noted
to induce altered development of Neural Stem Progenitor Cells, with the
potential to cause long-lasting cognitive
damage.117,118 The extrapolation of such evidence into
clinical practice is debatable, and further evidence is needed to make a
final statement on the developmental neurotoxicity of
ketamine.119 In fact, in the presence of harmful
stimuli such as pain and inflammation, ketamine, by its analgesic and
anti-inflammatory action, may even have a neuroprotective
role.120 Nonetheless, it would be prudent to practice
caution while administering ketamine to neonates, young infants, and
pregnant and lactating women, and prefer alternative agents.
Prospects for future research
There is ample evidence for ketamine as a good agent for procedural
sedation in children with cancer. However, regarding its role as an
analgesic, despite numerous reports from small studies and case reports,
there is a paucity of quality evidence. There is a clear need for
systematic well-designed studies to evaluate the efficacy and safety of
ketamine as an analgesic agent, including that of oral and local routes
of administration. Understandably, there are ethical concerns regarding
the conduction of a drug trial for end-of-life cancer pain. In such
circumstances, the clinician and parental tolerance for adverse effects
are much higher, allowing the use of a wider gamut of analgesic agents
and at higher doses. Ketamine has been successfully used in this setting
in children with terminal cancer.70,71 However, the
role of ketamine for the treatment of neuropathic pain in children with
cancer in non-terminal stages is still not convincing. There are
concerns regarding sustained efficacy as well as the potential for
neuropsychiatric adverse effects. This aspect requires further research,
preferably as a randomized controlled trial, to enable confident
prescription of ketamine by pediatric oncologists.
Conclusion
Ketamine is a dissociative anesthetic with an excellent analgesic action
at low doses. Due to its desirable effect on hemodynamics and protective
airway reflexes, it is commonly used for short term procedural sedation
as an intravenous drug. Other forms of systemic administration like oral
or intranasal routes have been proven to be safe and effective and have
the advantage of easy administration. Moreover, topical delivery of
ketamine has also shown encouraging results but still requires further
investigations, especially in children. Ketamine is a commonly used drug
in pediatric oncology practice, mostly for sedation, but its efficacy as
an analgesic is largely underutilized. Pediatric oncologists need to
familiarize themselves with the pharmacological aspects of the drug to
prescribe it more rationally and effectively, while keeping in mind the
possible, albeit rare, serious adverse effects.