The first reports of opioid use date to more than 6000 years ago, when a gummy substance known as opium was extracted from poppy plants known for its mind-altering effects. In 1805, a German chemist, Friedrich Serturner, identified the active ingredient in opium. He named it morphine, after Morpheus, the Greek God of dreams. In 1853, the hypodermic needle was introduced, and morphine could be administered intravenously. Morphine was used extensively during the American Civil War, and thousands of soldiers became addicted to the drug. In 1874, morphinewas modified by adding 2 acetyl groups to make heroin and in 1898 was marketed as a cough suppressant. In 1924, because of the addictive properties of opioids, nonmedical use was banned. In 1930, the synthetic opioid meperidine was introduced as an alternative to morphine to treat pain. During World War II another synthetic opioid, methadone, was developed as an alternative to morphine, and in the 1960s it was used as an adjunct to treat opioid addicts. In 1959, Janssen Pharmaceuticals developed another synthetic opioid, fentanyl, which was introduced into clinical care in 1960. Janssen went on to develop other fentanyl congeners, including sufentanil (1974) and alfentanil (1976). In 1992, Glaxo Smith Kline developed and marketed the newest of the fentanyl congeners, remifentanil.

Opioids activate opioid receptors present throughout membranes in the brain, spinal cord, and gastrointestinal system. Opioid receptors have been most extensively studied at synaptic junctions in the spinal cord. They consist of G protein–coupled receptors that activate ion channels and allow the flux of potassium and chloride, leading to a net negative polarization of a neuron membrane. In a hyperpolarized state, neurotransmission of pain signals are reduced especially in C and Aδ fibers that detect noxious stimuli.¹ The main types of receptors are presented in Table 5–1.² These receptors are similar; up to 70% of their protein sequence is identical. Other types of opioid receptors exist, but their role in pain control is not well defined.³

Opioids are administered intravenously as a bolus and/or a continuous infusion and by mouth. Sample intravenous dosing regimens for commonly used opioids are presented in Table 5–2. Dosing is often thought of as an absolute dose; for example, for postoperative pain control, 100 mcg of intravenous fentanyl is frequently used. This approach works well when most patients are about the same size (ie, 70–75 kg). As clinicians face a more diverse range in body weight, a more accurate approach is to normalize the dose to weight. Table 5–2 presents doses normalized to weight as well as common absolute doses.

Drug Preparation

With the exception of remifentanil, opioids are dispensed as liquid suspensions. Fentanyl, hydromorphone, and alfentanil are packaged so that they do not require dilution for an adult. Morphine, meperidine, and sufentanil are more concentrated and require dilution. Remifentanil comes as a lyophilized powder and requires dilution with normal saline. Because it is nearly equipotent to fentanyl, a common technique is to prepare remifentanil in concentrations of 20 to 50 mcg/mL. Opioid equivalencies are useful comparisons when considering different opioids to achieve a similar effect. Selected equivalencies are presented in Table 5–3.

Pharmacodynamic Models

Researchers have identified opioid concentrations that provide analgesia for a variety of noxious stimuli using pharmacodynamic models. Similar to minimum alveolar concentration levels, the C₅₀, defined as the effect-site concentration necessary to achieve an effect (ie, analgesia) in 50% of healthy adults, is used to describe opioid potency. C₅₀ concentrations have been most extensively studied with remifentanil. Remifentanil C₅₀ values have been identified for opioid effects to include various painful stimuli, ventilatory depression, and sedation (Table 5–4).

Simulations provide visualization of the magnitude and time course of drug concentrations (pharmacokinetics) as well as the onset and duration of drug effects (pharmacodynamics). For purposes of illustrating opioid effects, 2 effect measures will be used: the loss of response to 30 pounds per square inch of anterior tibial pressure and a respiratory rate less than 4 breaths per minute (see Table 5–4). The loss of response to tibial pressure is used as a surrogate of moderately painful surgical stimuli. Simulations will be used to explore the behavior of commonly used opioid administered as a bolus and as a continuous infusion.

Bolus Dosing

Using published pharmacokinetic models^{11,12,13,14,15, and16} and sample bolus doses presented in Table 5–2, simulations of a bolus of alfentanil, fentanyl, sufentanil, remifentanil, hydromorphone, and morphine are presented in Figure 5–1. Of note is the difference in the time required to reach the peak effect-site concentration (Table 5–5). The fentanyl congeners (remifentanil, alfentanil, and sufentanil) all share a similar profile; the effect-site peaks shortly after administration. Alfentanil and remifentanil require less than 2 minutes to reach their peak, and fentanyl and sufentanil require 4 to 6 minutes. After reaching their peak, effect-site concentrations wane over the next 30 to 40 minutes. Of the fentanyl congeners, remifentanil has the most rapid drop in effect-site concentrations, whereas fentanyl has the slowest.