Ketamine, a derivative of phencyclidine (PCP), is a dissociative anesthetic that has analgesic properties in sub-anaesthetic doses. Ketamine is the most potent NMDA-receptor-channel blocker available for clinical use, binding to the PCP site when the channels are in the open activated state. It also binds to a second membrane-associated site which decreases the frequency of channel opening.
The NMDA receptor-channel complex is closely involved in the development of central sensitization of dorsal horn neurons that transmit pain signals.4 At normal resting membrane potentials, the channel is blocked by magnesium and is inactive.3 When the resting membrane potential is changed as a result of prolonged excitation, the channel unblocks and calcium moves into the cell. This leads to neuronal hyperexcitability and results in hyperalgesia and allodynia, and a reduction in opioid-responsiveness. These effects are probably mediated by the intracellular formation of nitric oxide and cyclic guanosine monophosphate.
The reduction in opioid-responsiveness arises from cross-talk between opioid receptors and the NMDA receptor-channel. Opioid receptor activation results in phosphorylation and opening of the NMDA receptor-channel leading to a cascade of events that ultimately down-regulates the opioid receptor and its effects, thereby contributing towards tolerance and hyperalgesia.3
In addition to blocking the NMDA receptor-channel, ketamine has other actions, some of which may contribute to its analgesic effect.2 These include opioid-like and anti-inflammatory effects,5 and interactions with, e.g.:
•other calcium, potassium, and sodium channels, e.g. HCN, AMPA
•cholinergic, dopaminergic and noradrenergic transmission
•descending inhibitory pathways.
Resultant changes in cellular processes, e.g. in gene expression and protein regulation, could explain ongoing benefit even after discontinuation of ketamine.
Ketamine is generally administered PO or SC/CSCI.7. It can also be administered IM, IV, SL, intranasally, PR and spinally (preservative-free formulation). However, for spinal routes, concerns have been raised about the potential for neurotoxicity.17 Ketamine has been given by CIVI in adults and children in combination with opioids (fentanyl, morphine) ± midazolam to control intractable pain and agitation.
Although in some countries both racemic ketamine and the S−enantiomer are available for clinical use, in the USA only the racemic mixture is marketed. Because of its greater affinity and selectivity for the NMDA-receptor, the S−enantiomer as a parenteral analgesic is about 4 times more potent than the R−enantiomer, and twice as potent as the racemic mixture.
When equi-analgesic doses are compared, the S−enantiomer is also associated with lower levels of undesirable effects, e.g. anxiety, tiredness, cognitive impairment.
About 90% of a parenteral dose of ketamine is excreted in the urine, mostly as conjugates of hydroxylated metabolites. Less than 5% is excreted unchanged via the feces and urine. Ketamine undergoes hepatic metabolism mainly to norketamine. Because of extensive first-pass metabolism, a greater proportion of a PO dose of ketamine is converted to norketamine compared to one administered by injection.25 Norketamine has a lower affinity for the NMDA-receptor-channel than ketamine. Although norketamine (particularly S-norketamine) is analgesic in rodents, this remains to be clarified in humans. Norketamine is further metabolized to the inactive dehydronorketamine.
Ketamine causes hepatic enzyme induction and enhances its own metabolism. The implications of this for the efficacy or tolerability of therapeutic ketamine is unknown. However, in abusers, it may contribute towards the relatively rapid tolerance to the desired ‘high’, with those taking it most days of the week reporting about a 7-fold increase in dose after the first 2 months of use.
Ketamine increases sympathetic nervous system activity and causes tachycardia and intracranial hypertension. When ketamine is used for procedural anesthesia, a quarter of patients experience vivid dreams, misperceptions, hallucinations, and alterations in body image and mood as emergent (psychotomimetic) phenomena, i.e. as the effects of a bolus dose wear off.
Although it is used as an analgesic in various clinical settings (including postoperatively, the increasing concern about the potential for neuropsychiatric, urinary tract, and hepatobiliary toxicity will probably result in a decline in the use of ketamine for chronic non-cancer pain, and possibly cancer pain. In the palliative care setting, ketamine should generally be reserved for pain which has failed to respond to standard analgesic drugs, including opioids and adjuvants.
Ketamine for Chronic non-cancer pain
A review of sub-anesthetic doses of ketamine for chronic non-cancer pain (mostly neuropathic but also ischemic, fibromyalgia, post-whiplash, etc.) identified 29 RCTs and concluded that:
•ketamine provides relief
•undesirable effects can limit its use
•long-term use should be restricted to a controlled trial.35
A systematic review of analgesics for phantom limb pain reached similar conclusions. There is RCT evidence of benefit in complex regional pain syndrome type, with relief persisting 4–6 weeks beyond the duration of the ketamine infusion.
Ketamine for Cancer pain
A systematic review of ketamine as an adjunct to opioids in cancer pain found only two studies of sufficient quality13, 40, and concluded that there is insufficient robust evidence to assess potential benefits and harms.41 Thus, in patients with cancer, evidence of ketamine’s efficacy as an analgesic is mostly from case reports, retrospective surveys, or uncontrolled studies in patients with refractory neuropathic, bone, and mucositis-related pain. Results from a large RCT of PO racemic ketamine in cancer-related neuropathic pain are pending.
Short-term ‘burst’ treatment with ketamine may sometimes have a relatively long-lasting effect (i.e. several days to weeks and occasionally for months). For example, ketamine 100mg/24h by CIVI for 2 days in a cancer patient, repeated a month later, reduced opioid requirements by 70%. Similarly, in non-cancer pain, patients taking regular strong opioids for ischemic limb pain, a single 4h IV infusion of ketamine 600 microgram/kg reduced opioid requirements during the next week.
However, in a large case series, about a quarter of patients experienced severe undesirable effects from higher-dose ‘burst’ CSCI ketamine involving rapid dose escalation. Further, in a 5-day RCT in cancer patients using the same regimen, there was no difference in the proportion responding in the ketamine and placebo arms (about 50% in each, based on average pain score). There were fewer treatment failures at the maximum dose (25 vs. 50%) but more undesirable effects and withdrawals due to toxicity (19 vs. 2%).
Miscellaneous Ketamine Facts
PO/IV ketamine (generally in combination with morphine or midazolam) can provide analgesia in severe cancer treatment-related mucositis,59 during painful procedures, e.g. change of dressings and orthopaedic emergencies.
Topical ketamine has been applied to the skin in various non-cancer pains and used as an oral rinse in radiation-induced mucositis.
Ketamine Infusion Therapy has a rapid antidepressant effect in patients with major depression and bipolar disorder, including a reduction in suicidal ideation.
Following a single IV dose (typically 500 microgram/kg over 40 min), up to 70% of patients respond, with improvements seen within hours. However, the duration of benefit is generally less than one week.
These effects are accompanied by more rapid restoration of neuroplasticity than that seen with conventional antidepressants. The exact mechanism is unclear but includes the release of brain-derived neurotrophic factor which helps to restore neuroplasticity, e.g. through the formation of new synapses. Although case reports of benefit are emerging from the palliative care setting, the use of ketamine to treat major depression is experimental, and should ideally be restricted to RCTs. Other drugs that act on the NMDA receptor-channel complex are undergoing clinical trials in depression.
The use of CIVI ketamine has been explored in the treatment of refractory status epilepticus, but its place in clinical practice remains to be determined.
Dose and Use of Ketamine
Because of the undesirable effects profile of ketamine, which includes neuropsychiatric, urinary tract, and hepatobiliary toxicity, prescription of ketamine as an analgesic should be restricted to specialists in pain or palliative care for patients who have failed to obtain adequate relief from standard non-drug and drug treatments, including the optimal use of opioids, non-opioids, and adjuvant analgesics. A toxicity monitoring form is available.
In patients with a prognosis of more than a few weeks, once analgesia has been obtained, an attempt should be made to withdraw ketamine over 2–3 weeks. Benefit from a short course can last for weeks or even months and can be repeated if necessary.53 Thus, apart from patients with a prognosis of just days–weeks, long-term continuous ketamine should be used only as a last resort, i.e. in those patients with unsatisfactory analgesia from a short course approach.
JPSM, Journal of Pain and Symptom Management, Published by Elsevier Inc.