Opiates have profound and varied effects on the CNS. For example, large doses may induce excitation or seizures. Normeperidine, the principal metabolite of meperidine (Demerol), is well known to induce “pseudoseizures” particularly in individuals who have renal insufficiency. This is because the metabolite is long-lived in these circumstances, accumulates, and is cleared slowly. Opiates also suppress the cough reflex by direct activity on the medulla. Furthermore, through a direct effect on the brain stem (pons, medulla), opiates alter respiratory rhythm and voluntary control as well as decrease responsiveness to carbon dioxide tension. Normally, as arteriole carbon dioxide tension rises, cerebrovascular dilatation occurs, with the resultant increase in cerebral blood flow and cerebrospinal fluid (CSF) pressure. This response is diminished with the use of opiates, an effect that is much more likely with intravenous administration.

Another effect is nausea, which develops as a consequence of orthostatic hypotension or by direct stimulation of a chemotactic trigger zone in the medulla oblongata. Orthostasis may occur as a result of vasodilatation from histamine release or from the suppression of sympathetic outflow from the vasomotor medullary center. The medullary nuclei may also be stimulated to cause bradycardia. The one exception to this phenomenon is the opiate, meperidine, which is usually associated with tachycardia. Finally, there is increased vestibular activity observed with opiates as well.

As can be readily appreciated, there are numerous and profound effects produced by the administration of opiates. In addition to the foregoing, opiates increase smooth muscle tone throughout the gastrointestinal tract, including the gastric antrum, duodenum, large bowel, and the various gastrointestinal and biliary sphincters. When measured, the amplitude of nonpropulsive contractions is increased, but the intensity of propulsive contractions is decreased. The exception is meperidine. Whereas it does have some sympathomimetic (anticholinergic-like, atropine-like) effects, it may produce less smooth muscle spasm. Therefore, this drug should be considered the preferred opiate to use after bowel surgery because it is least likely to affect return of intestinal function. The effects are not always uniform with opiates, however. For example, biliary spasm does not always occur. Some individuals have no change in ductal diameter or pressure. Increased smooth muscle tone, resulting in reduce motility of the affected part, is variable according to the drug, being greatest for morphine, followed in order by methadone, meperidine, and codeine.

Another effect of opiates is increased tone of the bladder sphincter, impeding urination. There is also increased tone and contraction in the lower one-third of the ureter. Furthermore, tone of the detrusor muscle is increased, which may result in urinary urgency. Finally, opiates may increase secretion of vasopressin, a consequence of which may be oliguria.

Opiates can also have a profound effect on the endocrine system. Inhibition of the release of thyrotropin from the adenohypophysis leads to a decrease in thyroid hormone. Opiates may also produce hyperglycemia by stimulating receptors near the foramen of Monro or by releasing epinephrine. This may be associated with a decrease in the metabolic rates by about 10% to 20%.

The relative potency of the various opiates is summarized in Table 8-1.

Opiates are primarily metabolized by the microsomes in the endoplasmic reticulum of the liver. Additionally, metabolism also occurs in the CNS, kidneys, lungs, and placenta. This is accomplished by hydrolysis, oxidation, and conjugation with glucuronide.

All opiate receptors appear to function primarily by exerting inhibitory modulation of transmission of synapses in the spinal cord, the myenteric plexus, and the CNS. When located at a presynaptic terminal, these receptors act to reduce neurotransmitter release and, therefore, to decrease conductance. All appear to be linked to guanine nucleotidebinding regulator proteins (G proteins). Opioids regulate the so-called transmembrane signaling system—adenylate cyclase activity, ion channel activity, and the activity of phospholysasis or phosphoinositol. So-called kappa agonistic activity inhibits N-type voltage-dependent calcium channels, specifically in the myenteric plexus and the dorsal root ganglia. Stimulation of mu receptors in the locus coeruleus produces membrane hyperpolarization by an inward potassium rectifying current. The opioid receptors on terminals of afferent nerves in the CNS and in the spinal cord mediate inhibition of the release of neurotransmitters, including
substance P. Enhanced activity in descending aminergic bulbospinal pathways then exerts inhibitory effects on the processing of nociceptive information. Specifically, mu opioids in the ventral tegmentum activate certain dopaminergic and γ-aminobutyric acidergic neurons that project to the nucleus accumbens. This is the site that is postulated to be the central point producing opiate euphoria and the self-reinforcing effects well known to individuals familiar with addiction.³⁴

Within the intestinal tract, enterocytes themselves possess opioid receptors. As a consequence, opiates inhibit transfer of fluid and electrolytes into the intestinal lumen through their actions on the intestinal mucosa. Through effects on the submucosal plexus, there is a decrease in enterocyte basal secretion. Additionally, there is an inhibition of stimulatory effects of acetylcholine, prostaglandin E₂, and vasoactive intestinal peptides. The pressure of opiates at the periaqueductal gray or in the spinal cord will also inhibit gastrointestinal activity as long as the extrinsic innervation to the bowel is intact. This may explain why agents with poor penetration of the CNS (e.g., paregoric) can produce constipation at subanalgesic dosages.

Postoperative ileus is the temporary cessation of coordinated bowel motility, and its presence may prevent transit of bowel contents or tolerance of oral intake. Ileus is an expected occurrence after abdominal surgery; it usually lasts 3 to 4 days. It may be more prolonged if there is a complication such as an anastomotic leak. Endogenous opioids (endorphins, enkephalins, dynorphins) and prescribed opioids activate the mu receptor within the bowel and affect motility, secretion, and transport of fluids and electrolytes. The total dose of exogenous opioid administered correlates significantly with the return of bowel function as measured by the presence of bowel sounds, time to passage of first flatus, and time to first bowel movement. Return of bowel function also correlates with hospital length of stay.^5,10,45

Intravenous (IV) PCA, a technique that allows patients to medicate themselves, dates back to the mid-1960s. The development of electronic devices or pumps that deliver small amounts of medicine on demand has been an essential ingredient for the success of this pain management system. Improvements in device design have increased security and data output capacity, introduced error reduction programs, and offered a choice of electrical or battery power. Based on a literature review, Dolin and coworkers concluded that IV PCA provided better pain relief than intermittent IM opioid analgesia.¹⁸ Three meta-analyses have confirmed these results, although the magnitude of the differences was small.^2,30,59 Certainly, conventional forms of opioid administration, that is, given by nursing staff, can be as effective as IV PCA, but this requires patient care settings where the nurse-to-patient ratio is high. Typically, such a unit is an intensive care area, which is neither a cost-effective organization for all levels of patient care nor an acceptable use of nursing services.

In the postoperative setting, a PCA device is used primarily for the administration of opiates to alleviate pain. Usually, morphine, hydromorphone (Dilaudid), fentanyl, or meperidine is used. A PCA device can also be programmed for use with epidural infusions, patient-controlled epidural analgesia. The goal of the PCA is to administer more timely drug doses and thereby to enhance patient satisfaction. White suggested it may decrease the amount of drug administered because it is more closely matched to the painful activity or stimulus encountered.⁶¹ Others have shown that opioid consumption may be higher with IV PCA when compared with conventional opioid analgesia, but there does not appear to be a difference in the incidence of opioid-related side effects.^2,30 If morphine is used, the dosage range is from 1 to 3 mg/hour following abdominal surgery. Self-reporting scales that have been assessed with this drug note effective analgesia.⁶¹

The choice of agent is often a determination made by the surgeon based on his or her comfort level. Because of its roughly eightfold higher potency, faster onset, and greater lipid solubility (hence greater CNS penetration), hydromorphone (Dilaudid) is usually selected for more severe pain. Certainly, for those who require more close matching of drug delivery, time of onset, and proximity to painful stimulus, hydromorphone is a sound alternative. Owing to the accumulation of a normeperidine metabolite, meperidine (Demerol) at the usual clinical doses is recommended by many individuals familiar with pain control only when the specific advantages (sympathomimetic anticholinergic properties, known anaphylaxis to alternative opiates, etc.) outweigh this disadvantage. The use of fentanyl in PCA should be approached with caution. Although its potency, speed of onset, and density of analgesic action are perhaps desirable, the likelihood of respiratory suppression, accumulation of drug-inhibiting gastrointestinal function, and sedation limit this opiate to management by only those specially qualified.

In initially programming a PCA device, a target hourly “safe” dose should be selected. Then, the “demand” and “interval time” can be set according to the half-life alpha distribution times and times to peak analgesia. Morphine is typically set at 1 mg every 8 minutes. This results in a maximum dose of 7 mg/hour. The peak effect of morphine occurs in about 10 minutes after intravenous administration. Less than 0.1% of intravenously administered morphine enters the CNS at the time of peak plasma concentrations.⁴² Therefore, the demand interval is set slightly less than that. The peak effect of hydromorphone is approximately 5.5 minutes; its interval is set at about 3 to 4 minutes. The total analgesic administered per hour is dependent on the volume of distribution, acid-base status, plasma protein-binding capacity, ventilatory mechanics, cerebral blood flow patterns, and presence of metabolic abnormalities (e.g., hypothyroidism), as well as a number of other subtle factors.

One should certainly consider the use of basal infusions when using PCA. In monitored areas such as intensive care units or operating suites, overdosing can be quickly recognized and treated. Because basal (continuous) infusions are not patient regulated, sedation and other side effects may accumulate rapidly; therefore, this method should be used with caution in less monitored patient care areas. Although one may achieve more “stable” pharmacologic plasma levels by the use of basal infusions, annoying pruritus, nausea, and prolonged ileus may result.

The choice of opiate depends on the volume and the route of administration, the side effects and toxicities, and the physiologic factors of the individual that affect drug excretion. For example, fentanyl has a membrane-stabilizing influence that may potentiate the activity of local anesthetics.

Alternatively, with respect to its anesthetic effectiveness, morphine may be more desirable when a greater spread involving more dermatomes is necessary. This is because of morphine’s hydrophilicity and lack of segmental spinal cord binding (lipophilic binding). Ultimately, the surgeon uses whichever agent he or she feels most familiar with and most comfortable.

Complications relating to the use of PCA can be operator related, patient related, equipment related, and those secondary to the agent chosen. The most common operator-related complications are (in decreasing frequency) improper opioid dose or quantity, unauthorized drug, omission error, and prescribing error (wrong drug, inappropriate use of concurrent medications).⁵⁷ Approximately 30% of all PCA errors may result from incorrect programming of PCA pumps, which is twice as likely to cause injury or death than mishaps involving general-purpose infusion pumps.²¹ Innovations applied to avoid this include systems that use internal software to check the doses prescribed against preset limits. The programmer is then alerted. Patient-related errors may be offset by proper initial education and by limiting access to the drug reservoir and microprocessor program with the use of a key or access code. This may reduce tampering by family members.

Opioid side effects include respiratory depression, nausea and vomiting, and pruritus. Risk factors for respiratory depression include the use of continuous (background) infusions, concurrent administration of sedatives, advanced patient age, and hypovolemia. The addition of antiemetics directly to the PCA solution is controversial; perhaps separate administration is preferable and allows more accurate dosing.