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.