Neuraxial Administration of Opioids for Pain Therapy

Aside from the intermittent or continuous local neural blockade, such as intercostal nerve blockade or infusion of a local anesthetic through an interpleural catheter, spinal/epidural analgesia is an effective technique to be used in postoperative pain therapy. Neuraxial drug administration describes techniques that deliver drugs in close proximity to the spinal cord, i.e. intrathecally into the cerebrospinal fluid (CSF) or epidurally into the fatty tissues surrounding the dura, by injection or infusion. This approach was initially developed in the form of spinal anesthesia over 100 years ago. Since then, neuraxial drug administration has evolved and now includes a wide range of techniques to administer a large number of different drugs to provide anesthesia, but also analgesia and treatment of spasticity in a variety of acute and chronic settings. This is usually done using an epidural opioid and/or local anesthetic injected intermittently or infused continuously.

Use of spinal analgesia, neural blockade or the infusion of local anesthetic through interpleural catheters require special expertise and well-defined institutional protocols and procedures for accountability. Administration of regional analgesia is best limited to specially trained and knowledgeable staff, typically under the direction of an acute or postoperative pain treatment service

Rationale for application of opioids into the epidural/intraspinal space is opioid receptors, which are not only found in the supraspinal area. They are also found in the dorsal horn of the spinal cord (lamina I and the deep layers V-VI; Figure III-69),

Substance P

Substance P

Figure 111-69. Localization of substance P, metencephaline and opioid receptors in lamina I and II in the substantia gelatinosa of the spinal cord, where 90% are |-receptors, 7% are S-receptors and 3% are K-receptors. Within the central canal, receptor distribution is 65% for the 33% for the S- and 2% for the K-type (Adapted from [209])

Opioid receptor

Central canal

Figure 111-69. Localization of substance P, metencephaline and opioid receptors in lamina I and II in the substantia gelatinosa of the spinal cord, where 90% are |-receptors, 7% are S-receptors and 3% are K-receptors. Within the central canal, receptor distribution is 65% for the 33% for the S- and 2% for the K-type (Adapted from [209])

being responsible for the mediation of an analgesic effect. There nociceptive affer-ences are transmitted via interneurons to the spinothalamic, which projects to higher cortical areas such as the brain stem (medulla, pons), and to midbrain areas, which synapse to the ventroposterior and intrathalamic nuclei of the thalamus. Projections from the thalamus finally terminate in the primary somatosensory cortex (S1 and S2 region).

At the level of the spinal cord, nociceptive impulses can be modulated by afferent signals from peripheral touch receptors. Within the spinal cord, nociceptors release glutamate and substance P in layers I and II (substantia gelatinosa) and III where they stimulate both excitatory NMDA, AMPA, glutamate and neurokinin NK1 receptors (Figure III-70). At the same time the substantia gelatinosa is the site, where endogenous opioids are being released, which regulate the release of excitatory transmitters.

As a consequence of NMDA receptor activation, two potent mediators of pain, nitric oxide (NO) and adenosine are released. If, however, opioids are applied in that area they are able to reduce the release of pain mediators resulting in an inhibition of afferent activity. Neuraxial opioids are able to produce a sufficient analgesic effect in both surgical and non-surgical pain. Contrary to the sole application of local anesthetics for the treatment of pain, injection of an opioid close to the spinal cord results in lesser sensory, sympathetic or motor inhibition. As a consequence there is lesser orthostatic hypotension and there is no risk in loss of motor coordination.

The advantage of a neuraxial application of an opioid especially is of benefit in patients with preexisting pulmonary, cardiovascular disease, the extreme obese patient, and the elderly patient population undergoing major operations [210]. The neuraxial opioid application, contrary to an intramuscular or an intravenous dose, is characterized by a longer duration of action and a lesser dose, necessary for blockade

Figure 111-70. Following peridural application, opioids diffuse to the lamina V where opioid receptors are unevenly distributed with 70% for the p-, 20% for the 8- and 2% for the K-type

of nociception. However, when compared to intravenous or intramuscular mode of application, there is no proof for superior quality of analgesia following epidural or intrathecal opioids. Also, possible neurotoxicity and incompatibility of the agent with the cerebrospinal fluid has to be anticipated. This is why the neuraxial application of an opiate like opium and an opioid like remifentanil is banned [211, 212].

The major indication for use of neuraxial opioids is postoperative pain following orthopedic, intraabdominal, and thoracic or perineal operations. In the intensive care situation a patient with a flail chest as well as the polytraumatized patient, where repetitive evaluation of consciousness is of importance, analgesia by means of an epidural catheter is an advantage when compared to systemically-induced analgesia and sedation [213].

The benefits of adding an epidural opioid for alleviation of pain are as follows:

• a highly selective blockade of noiceptive afferences

• a maintenance of motor control, no loss of deep sensory and temperature sensations

• a long duration of action

• a potentiation of action when applied with a local anesthetic

• a regional distribution

• a lesser dose for efficacy (20%-25%) when compared to systemic application

• a lesser incidence of side effects.

There are following indications for neuraxial opioids in acute and chronic pain syndrome:

1. Terminal tumor pain

2. Excessive dosages for pain relief with oral opioids

3. Inefficiency of oral opioids

4. Severe side effects during oral opioid

5. Prolonged postoperative pain therapy.

6. Cesarean section

7. Visceral pain during the first stage of labor

8. Potentiation of peridural analgesia with a local anesthetic

9. Prolongation in duration of action of local anesthetics.

Opioids suitable for a neuraxial application (Table III-19) should have the following physicochemical and pharmacokinetic properties [214]:

1. A high affinity to the opioid receptor site with concomitant high analgesic potency.

2. High lipophilicity, which enables the drug to quickly pass the dura mater and accumulate in the spinal cord tissue.

3. A low hydrophilic property with a lesser time of stay in the cerebrospinal fluid.

4. A high molecular weight with increased absorption in the surrounding tissue [215].

5. A long duration of receptor binding, with a concomitant long duration of action.

6. A low incidence in the development of tolerance followed by low habituation. Due to the different physicochemical properties, there is a different mode of action of opioids following neuraxial application. Since the diffusion rate from epidural space into the spinal tissue and the blood stream mostly depends on lipophilicity, fentanyl has a faster onset of action than the hydrophilic compound morphine. However, at the same time, the duration of action of fentanyl is much shorter. This is because morphine has hydrophilic properties, which results in a delayed diffusion into spinal cord tissue and at the same time demonstrate a slowed rediffusion out of the spinal cord (Figure III-71).

While the long duration of action of morphine is due to its hydrophilic property, the long duration of action of buprenorphine is due to its intense receptor binding.

Table 111-19. Summary of opioids used for neuraxial application

Opioid generic name

Opioid trade name

Mean epidural dose (mg/70 kg)



















Morphine Sulfate




















Fentanyl !

4 6 8 Duration of analgesia

4 6 8 Duration of analgesia

Figure III-71. Comparison of onset time and duration of action of different opioids used for peridural analgesia (Adapted from [214, 216])

This results in a slow dissociation from its binding site. Morphine when being injected into the cerebrospinal fluid with a physiologic pH, 75% is present as morphine-hydrochloride showing little tendency to diffuse into spinal tissue. The residual 25% are present as a base, which rapidly diffuses through the dura mater and into the substantia grisea of the spinal cord, the genuine site of action. Following diffusion equilibrium is established. Since the hydrophilic morphine hydrochloride very slowly diffuses out of the liquor, it stays within the epidural space where it acts as a reservoir, contributing to the long duration of action (Figure III-72).

Only morphine and sufentanil are legitimated for epidural or intrathecal use. If other opioids are utilized for neuraxial application this is done under the sole responsibility of the physician

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