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Multi-drug protocols · Clinical background

MLK CRI (Morphine + Lidocaine + Ketamine)

Multimodal analgesic CRI combining a µ-opioid agonist (morphine), a sodium-channel blocker with antihyperalgesic and prokinetic properties (lidocaine), and an NMDA receptor antagonist (ketamine). The three drugs target different pain pathways simultaneously, reducing the dose required of any single agent and providing broader-spectrum analgesia than monotherapy.

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Clinical background

The MLK protocol, morphine, lidocaine, ketamine, is one of the most widely used multimodal analgesic CRIs in canine critical care. It combines three drugs that act at different points in the pain pathway, producing additive or synergistic analgesia at lower doses of each individual agent than would be needed for monotherapy. The protocol is dog-only by design.

What the protocol does

The recipe (per Silverstein 134.1) is straightforward: 10 mg morphine + 150 mg of 2% lidocaine (= 7.5 mL) + 30 mg ketamine into a 500 mL bag of lactated Ringer’s solution, infused at 10 mL/kg/hr. At that fixed administration rate, the patient receives:

Each component sits at the standard analgesic CRI dose for that drug, these are not subtherapeutic doses combined for synergy; they’re full doses that happen to be additive when delivered together.

Why combine three drugs

Pain is a complex signal with multiple processing nodes. Each drug in MLK addresses a different node:

The combination addresses peripheral nociception (lidocaine), spinal-level transmission (morphine), and central sensitization (ketamine) at the same time. Compared to monotherapy, each component can sit at standard doses without the side-effect burden that pushing any single drug to high analgesic effect would cause.

Indications

Primary use cases:

Why this protocol is dog-only

Each component has a cat-specific concern that, taken together, makes the combination unsafe:

For cat multimodal analgesia, consider fentanyl + ketamine (with or without dexmedetomidine), or fentanyl alone.

Administration

The fixed administration rate of 10 mL/kg/hr is a feature of the protocol, not a limitation, the bag concentration is calibrated so that this rate delivers all three drugs at their analgesic doses simultaneously. Do not change the rate to increase or decrease analgesia; if the patient needs more analgesia, add an opioid bolus or a separate ketamine bolus rather than running the bag faster.

The lactated Ringer’s carrier serves dual purpose as the analgesic vehicle and as a maintenance-rate fluid. At 10 mL/kg/hr, the rate exceeds standard IV maintenance (≈2–4 mL/kg/hr), be aware of this in patients with cardiac disease, renal disease, or any condition where fluid loading is a concern. In those patients, either reduce concurrent fluids being run on a separate line or use a different multimodal protocol that doesn’t lock fluid rate to drug rate.

Use 2% lidocaine WITHOUT epinephrine (20 mg/mL plain). Lidocaine-with-epinephrine is sold for dental and local infiltration; mixing it into the MLK bag would deliver an unintended epinephrine bolus and is a serious medication-error risk.

The bag is stable for 24 hours at room temperature and 7 days refrigerated per typical compatibility data. Most institutions prepare fresh daily.

Loading and breakthrough

The MLK bag itself has no loading dose, the CRI takes time to build effective plasma levels of each component. For a planned MLK start, give the patient an opioid bolus (morphine 0.1–0.2 mg/kg IV slowly, or hydromorphone 0.05–0.1 mg/kg IV) about 15–30 minutes before starting the bag. For breakthrough pain during MLK, give an opioid bolus rather than increasing the bag rate.

Adverse effects

The MLK profile combines dose-related effects of all three components:

Have naloxone immediately available for opioid reversal and IV lipid emulsion 20% available as the lidocaine-toxicity antidote. Both should be drawn up and ready for any patient on a sustained MLK infusion.

Drug interactions

Monitoring

Stepping down

When the patient is comfortable on the MLK and a transition plan is in place, step down in this order: lidocaine first (reduces toxicity-monitoring burden), then ketamine, then taper the opioid component as appropriate to the underlying pain process. Many patients can be transitioned from MLK to oral analgesia (NSAID + tramadol or gabapentin where appropriate) over 24–48 hours.

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