Sedation and analgesia II: Opioids

The second in a multipart series on the basics of ICU analgesia and sedation. Start with Part I: Principles to learn about our three fundamental rules.

Let’s touch upon a couple of important pharmacologic concepts, then discuss some specific drugs.

When short-acting isn’t

Some drugs we’ll discuss, such as fentanyl, are considered fast-on, fast-off. In many cases, this is because of their high lipophilicity, which lets them rapidly leave the bloodstream and enter the tissues.

Here’s the caveat: these pharmacokinetics only hold true with occasional, intermittent use. If you deliver these drugs in prolonged infusions, or in frequent, regular boluses, you can saturate the lipid-rich tissues until they turn into a drug depot. Once you turn off the drip, the drug continues to leach back out into the bloodstream for many hours.

In other words: a push of fentanyl or midazolam doesn’t last very long. But a high-dose drip left running for a week? That may take days to clear.

When hemodynamically stable isn’t

When we push a drug on a patient in shock and their blood pressure drops, why did it happen? Sometimes, it is due to intrinsic effects of the drug, such as the histaminergic impact of morphine. However, “pure” synthetics like fentanyl should have little effect on the heart and vessels in someone with normal cardiovascular physiology. And yet, push it on the shocked patient, and they may still tank. Why?

The fact is that even intrinsically stable drugs can still have sympatholytic effects. A patient in shock is compensating with their intrinsic sympathetic drive, sustained by their ongoing release of fight-or-flight hormones. Blunting pain or tamping down the level of consciousness will predictably suppress this compensatory response, just like getting Usain Bolt drunk will bring down his 100 meter time. Thus, any analgesic or sedative can cause decompensation in shock.

A classic examples would be the young patient after trauma or sepsis. He looks well, with a normal blood pressure and good signs of perfusion, and merely shows some subtle signs of compensation like tachycardia. You blithely give a dose of a “neutral” drug like fentanyl or etomidate, and suddenly his BP drops like a rock. By defraying his compensatory response, you unmasked his shock.

Beware this, expect it, and significantly reduce all of your sedative and opioid doses in shock.

Morphine

Let’s talk opioids.

The older opioid drugs are naturally derived, or “true” opiates, produced from the poppy plant. The most common is the venerable morphine. IV morphine, either by push or continuous infusion, lasts a few hours and can offer potent analgesia by the simplest of mechanisms: direct binding of the mu receptor. However, it is a fairly “dirty” drug, associated with histamine release which can cause itching, nausea, and hypotension. First-generation histamine blockers like diphenhydramine (Benadryl) can easily combat this.

Morphine works, and many experienced clinicians are comfortable with it. But for my money, there is a limited role for morphine in the modern era. The synthetic opioids are cleaner, with fewer side effects and less hemodynamic impact. Outside of resource-limited settings, where it may be the only thing available, there are perhaps two indications where it still prevails:

1. Morphine is often used in hospice patients to reduce pain and air hunger at the end of life.
2. Due to its aforementioned side effects, some providers perceive it to have less risk for abuse among susceptible patients compared to its common synthetic alternative, hydromorphone—which tends to produce a very clean, euphoric high. Comparably, morphine is not as fun. This may also apply to the long-acting oral MS Contin versus the otherwise very similar oxycontin.

Dosing as a push is usually 1–10 mg, or about .05–.1 mg/kg.

Hydromorphone

We can now turn to our first synthetic opioid, hydromorphone (trade name Dilaudid). In use and duration of effect, it is similar to morphine, with a relative potency somewhere in the neighborhood of 1:8 (1 mg of hydromorphone to 8 mg of morphine). Thus, we would usually push somewhere between .2 mg and 1 mg. Of note, there is a phenomenon where many providers are inclined to give “too little” morphine (one or two milligrams when as much as 10 might be needed) yet “too much” hydromorphone (thinking nothing of pushing 1–2 mg when a dose this potent can easily cause adverse effects).

As mentioned, abuse is not uncommon: opioid-abusers are notorious for presenting to the emergency department asking for Dilaudid by name, administered in the most enjoyable form (pushed fast, perhaps with a Benadryl chaser). This is a major problem in many EDs, although somewhat removed from the typical ICU concerns.

On the other hand, it is a clean, effective analgesic, and very potent. Although in theory all opioids should offer equivalent analgesia at equipotent doses, many of us have the perception that hydromorphone is simply “stronger medicine” and often works for patients who find no relief from alternatives like fentanyl.

Fentanyl

The short-acting synthetic little brother to Dilaudid is fentanyl. The power of fentanyl is in its brevity: its onset is within minutes and its duration little more than an hour. This makes it ideal for quick bursts of analgesia, such as during procedural sedation. Indeed, quick dissipation along with its clean effect profile makes it the safest choice for any critically ill, hemodynamically unstable patient who may have an uncertain response to opioids. Stable, short-acting drugs with focused effects are what we want for sick people, and fentanyl is precisely that.

Pushes of fentanyl from 25 mcg to 100 mcg are effective for procedural pain. The same dose given q1h–q2h PRN is a great option for gentle intermittent analgesia in ICU patients with little reason to have significant pain—meaning many of them, even some who are intubated. For greater needs, use a fentanyl drip at 25–200 mcg/hour.

Remifentanil is a similar agent, incredibly short acting, and with less tendency to accumulate. However, it is not cheap, and relatively uncommon in the ICU setting in the US, although it is seen more so in the OR and overseas.

Patient-controlled analgesia

PCA pumps are often used as a “last resort” for difficult-to-manage pain. However, they are a reasonable solution for anybody requiring high doses of IV opioids. Their power is in their built-in control: unlike a continuous opioid infusion, which is usually unsafe in non-intubated patients since it can lead to obtundation and apnea, a PCA stops delivering if the patient becomes too sleepy to press the button. Any patient sufficiently awake—i.e. not altered or over-sedated—can use a PCA, even on the vent.

Fentanyl, hydromorphone, and morphine can all be delivered by PCA. They are configured with the following settings:

• The drug (e.g. hydromorphone)
• Continuous rate: A background infusion rate. This is usually not used, since it defeats the purpose of the PCA. It is mostly used as a basal replacement for patients dependent on chronic opioids.
• Demand dose: The dose delivered when the button is pressed (e.g. 0.2 mg)
• Lockout interval: The duration between allowed demand doses (e.g. 15 minutes)
• Maximum hourly dose: The total dose within an hour, e.g. 1 mg. This can be set instead of the lockout interval, or vice versa, but some pumps will ask you to set both, even though they are usually redundant.

Oral opioids

In the acute phase, our sick patients tend to get IV opioids. But once they have stabilized somewhat and are able to take enteral meds, transitioning the bulk of their regimen to oral meds will reduce cost and complications.

The best choice may be oxycodone, which is synthetic, affordable, and effective. Starting with a scheduled dose of 5 mg q4–q12 hours, and titrating up from there, you may be able to wean patients with persistent pain off their drips. For those with less pain, a PRN dose can be effective, perhaps still with a backup IV option (fentanyl or hydromorphone) for breakthrough or procedural pain. Remember, however, that you cannot simply have two PRN pain medications ordered, as this violates Joint Commission rules; you will need instructions for when to use which drug, such as a pain scale, first- and second-line designations, or your hydromorphone ordered explicitly “for pain not relieved by oxycodone.”

Oxycodone is often packaged with acetaminophen in combination pills (e.g. Percocet). These are best avoided in the ICU for two reasons. Combo pills increase the risk of overdose (from inadvertently combining multiple acetaminophen-containing drugs). But more importantly, separating the drugs allows the delivery of a maximal, standing dose of acetaminophen without interfering with the intermittent dosing of oxycodone. Once the patient stabilizes and their pain resolves, they can be transitioned to a combination pill for simplicity.

An even better choice for stable pain requirements is a long-acting oral agent, such as extended-release oxycontin or MS contin. Dosing is essentially equivalent to the short-acting oxcodone or morphine (respectively), but with a slow, steady release. Start with 10–15 mg, scheduled q8h–q12h.

Next time in Part III, multi-modal analgesia with non-opioid options.