Ketamine and analgesia – Not just an anesthetic anymore (Proceedings)

The neuro-anatomic, physiologic, and molecular basis of nociception is a rapidly evolving field of study. Much of the "action" in developing new targets for pain management therapy is in the dorsal horn of the spinal cord. Here the peripheral nociceptive signal of the primary afferent neuron is modulated, that is either enhanced or dampened, at its synapse with second-order or interneurons. Where primary afferent neurons terminate in the dorsal horn, they release various highly bioactive molecules across synapses to interneurons. Chief among many of these in the classic model is the excitatory amino acid glutamate, which binds to AMPA receptors on the interneuron. This binding causes a sodium/potassium channel to open, allowing Na+ to flow freely through the cell membrane into cytoplasm (and K+ out into the extracellular space), which elicits an action potential: the interneuron depolarizes and the impulse is transmitted afferently to the brain. However, as quickly as it opens, an AMPA receptor will close, unless the stimulus is sustained. If the stimulus is in fact sustained, not only will the AMPA receptor remain open, but the accumulation of intracellular Na+, will phosphorylate adjacent NMDA receptors, releasing a magnesium "plug." The NMDA receptor is now open and free to allow calcium to inflow into the neuron, further depolarizing it for an extended period of time. NMDA activation is now well-established in its role of potentiating hypersensitization and neuropathic pain.

The second-order, or projection neurons, upon which the peripheral A- and C-fibers synapse, are characterized as wide dynamic range (WDR, sensitive to a variety of sensations, including pain) and nociceptive-specific (NS, pain-only) neurons. They ascend the spino-thalamic tract to terminate in the thalamus, with projections (via third-order neurons) to the reticular, limbic, homeostatic-control, and cortical somatosensory regions of the brain Here the spatial and temporal qualities of pain become more than an unpleasant sensation, but transcends to a physical and emotional experience as well.

Sustained nociception begins to alter the dynamic considerably, and pain can quickly move from its physiologic, protective nature to a maladaptive one. The constant presence of inflammatory and bioactive mediators at a peripheral site forms a "sensitizing soup" that creates a constant barrage of excitatory neurotransmitters in the dorsal horn. The opening of the NMDA calcium channel begins a cascade of events that in some cases becomes irreversible. An influx of calcium ion causes activation of Protein Kinase C (PKC), which in turn elicits production of nitrous oxide (NO), which then diffuses back across the synapse and through the terminal ending of the afferent nociceptor. This causes K+ channels to close and also the production of Substance P, a profoundly excitatory bioactive molecule, which then flows back across the synapse once more to bind on neurokinase (NK-1) receptors of the interneuron (expression of the NK-1 receptor appears to also contribute to opioid-induced hyperalgesia and tolerance). Not only does the interneuron stay depolarized, but a phenotypic change may be induced where it may not reset. Expression of c-fos, c-jun, and Knox-24 genes transcribe new (probably aberrant) proteins that produce permanent microstructural changes of the neuron that result in reduced firing threshold, upregulation of central neuronal activity, downregulation of inhibitory activity, expansion of the receptive field, peripheral hypersensitivity and intensified pain responses to further stimulation

Historically, the focus of analgesia has been to diminish transduction (e.g. local anesthesia, anti-inflammatories) and perception (e.g. opioids), and indeed these remain crucial components of a multi modal approach to pain management. The most exciting area of attention today however is in the dorsal horn, by enhancement of inhibitory modulation of nociception and interrupting the feedback loop that results in exaggerated pain responses and perception. As greater understandings emerge of the molecular and physiologic bases of pain emerges, new opportunities for intervention also emerge.

Ketamine is a phencyclidine dissociative anesthetic; most commercial products exist as racemic mixtures of enantiomers. Its mechanism of anesthesia (and in humans, amnesia) is not fully understood but is thought to be achieved by functionally disrupting the CNS through over stimulation and/or inducing a cataleptic state. The evidence is building for its pre-emptive and preventive effects when given at subanesthetic doses in an intravenous constant rate infusion.

Ketamine binds to many receptor sites in the central nervous system. For its analgesic effects it appears to bind to a phencyclidine receptor inside the NMDA receptor, i.e. the calcium channel would already have to be open and active for ketamine to exert its effect. However, once bound, it decreases the channel's opening time and frequency, thus reducing Ca+ ion influx and dampening secondary intracellular signaling cascades. Hence it is unlikely (and has not been shown) to be truly analgesic in nature. Rather, it appears to be protective against hyperalgesia and central hypersensitization in the post-operative setting. This can be important not only to reduce immediate post-operative morbidity, but in humans acute postoperative pain is followed by persistent pain in 10-50% of individuals after common operations, such as groin hernia repair, breast and thoracic surgery, amputation, and chronic pain will be severe in about 2-10% of these patients.

Various studies in humans and rodent models utilizing ketamine via constant rate infusion or transdermal patch revealed that actual pain scores are not lowered significantly, but:

• Opioid consumption reduced by 30%

• Improved rehab after arthroplasty

• Reduced analgesic drug requirements after abdominal Sx, gynecological Sx

• Superior to intermittent morphine for musculoskeletal trauma

• Dose-dependent analgesia for M3 extraction

• Rescue analgesic in opioid-tolerant and opioid-hyperalgesic patients

• Reduces phantom-limb pain post-amputation?

A recent review of the human literature regarding the clinical properties of ketamine revealed the following evidence-based characteristics:

Level 1 evidence (Meta-analyses):

• considered to have "Preventive" rather than "Pre-emptive" effects in acute post-op period

• Opioid-sparing

• Safe

• Most effective as low-dose CRI for acute pain mgmt

Level II evidence (>1 properly-designed randomized clinical trial)

• Most effective as "anti-hyperalgesic," "anti-allodynic," or "tolerance-protective" treatment

• Effective as rescue analgesic for opioid-tolerant pts

• Reduces periph neuropathic, spinal cord injury pain

• Improves fibromyalgia symptoms

• IN route reduces breakthrough chronic pain (cancer and non-cancer)

• Does not improve local blocks

In the dog, studies have demonstrated have demonstrated the isoflurane and sevoflurane-sparing effect of CRI ketamine, and another demonstrated decreased withdrawal reflex after IV bolus followed by CRI ketamine. In cats, ketamine has been shown to demonstrate a CRI propofol-sparing effect. In a pair of clinical studies in dogs, one has demonstrated a positive effect of CRI ketamine following forelimb amputation, and another post-mastectomy.

Ketamine CRI is easily accomplished by 60 mg (0.6 ml of 10 mg/ml solution) per liter of fluids; fluids administered at standard intra-operative rates of 10 ml/kg/hr delivers ketamine at 10 mcg/kg/min. For a 20 kg dog in a 30-min. procedure, this represents pennies' worth of ketamine, It has been recommended to administer a loading dose of 0.5 mg/kg prior to CRI in order to ensure the rapid achievement of serum steady state. Ketamine is a controlled drug so bags of fluid should be discarded between patients.

Ketamine is one of the most potent NMDA-blockade drugs that can be deployed, which accounts for its anti-central hypersensitization and anti-hyperalgesic effect. Due to its low cost, high-safety margin at sub-anesthetic doses, it is a useful adjunct to any surgical procedure.

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