Intraspinal Opioids

CHAPTER 41 INTRASPINAL OPIOIDS



Zahid H. Bajwa, MD, Stephen A. Cohen, MD, MBA, Carol A. Warfield, MD, Gary McCleane, MD




1. What is meant by intraspinal opioid?


This term intraspinal opioid refers to the application of opioid medications in close proximity to the spinal cord in contrast to systemic (oral, intramuscular, intravenous) administration. Whereas intraspinal opioids act primarily on the spinal cord, the primary site of action for systemic opioids has been shown to be supraspinal receptors in the brain.



2. How are intraspinal opioids given?


Intraspinal opioids may be injected into the epidural space (outside the dura mater) or into the intrathecal space (subarachnoid or spinal). Either method may be single-shot or continuous. With single-shot administration, the spinal or epidural needle is withdrawn following injection. For continuous administration, a small catheter is placed, and the drug is given via the catheter. Drugs may then be administered by intermittent bolus or via a continuous infusion device.



3. How long have intraspinal opioids been in use?


In 1855, the Wood needle allowed for the first parenteral administration of morphine. However, it was not until 1979 that Wang, Nauss, and Thomas reported the first human study demonstrating the safe, effective intrathecal application of morphine. Behar and associates reported epidural applications soon after.



4. What is the rationale for using intraspinal opioids?


Nociceptive input (i.e., a painful stimulus) travels to the spinal cord via primary afferents, A-delta fibers, and C fibers. These fibers synapse with second-order neurons located in the dorsal horn of the spinal cord. From there, nociceptive input is transmitted to supraspinal centers in the brain via ascending tracts.


Melzack and Wall’s gate control theory proposed that interneurons in the dorsal horn act to modulate nociceptive input. They postulated that gates could be opened and closed by stimulation and inhibition via interneurons in the spinal cord. These interneurons were later determined to be located in the substantia gelatinosa. Spinal opioids exert their inhibitory primary effects in the substantia gelatinosa (lamina II) of the dorsal horn.



5. What evidence is there for opioid action in the substantia gelatinosa?


Iontophoretic, microinjection, and patch-clamp data have demonstrated that the substantia gelatinosa is the primary site of action for intraspinal opioids. Radioautographic studies have confirmed the presence of specific opioid binding in the substantia gelatinosa. The mechanism in the substantia gelatinosa is presynaptic inhibition of neurotransmitter release, although postsynaptic effects probably play a role.



6. How do opioids reach the substantia gelatinosa?


Once administered, subarachnoid opioids reach the spinal cord via two mechanisms: (1) direct spread from the cerebrospinal fluid (CSF), and (2) vascular absorption from the CSF, which is then delivered to the spinal cord. For epidural routes, opioid enters the CSF via direct spread through the dural cuff and then reaches the cord by the two mechanisms described above. Vascular absorption from the epidural space with subsequent delivery to the spinal cord also occurs.



7. Which specific properties of the opioid molecule play a role in reaching the dorsal horn?


Several pharmacokinetic properties determine the degree to which intraspinal opioids reach the dorsal horn: lipid solubility, molecular weight and shape, surface area exposed (i.e., “spread”) (Fig. 41-1), and route of administration (epidural vs. subarachnoid). The most important of these appears to be molecular weight.


image

Figure 41-1 Cross-section depicting opioid spread in epidural space (white arrows) and in spinal cord and cerebrospinal fluid (black arrows).


(From Cousins M, Bridenbaugh P, editors: Neural blockade in clinical anesthesia and management of pain, Philadelphia, 1998, JB Lippincott, with permission.)



8. Are all opioids created equal?


No. The most useful property for classifying intraspinal opioids is lipid solubility. Opioids can be divided into two classes: lipophilic (lipid-soluble) versus hydrophilic (lipid-insoluble). Examples of lipophilic opioids include fentanyl, sufentanil, and meperidine. Morphine and hydromorphone are hydrophilic. The octanol water coefficient is the standard for grading and comparing lipophilicity (Table 41-1).


TABLE 41-1. Relative Octanol: Water Coefficients (Compared to Morphine)





















Opioid O:W
Morphine 1
Hydromorphone 4
Meperidine 40
Fentanyl 400
Sufentanil 1600


9. What pharmacodynamic role does lipophilicity play?


Increased lipid solubility decreases the time required for transfer of drug across lipid barriers (blood vessels, cell membranes). Clinically, this translates to more-rapid onset, shorter duration of action after spinal administration, higher equianalgesic doses, and higher incidence of systemic side effects.



10. Why are higher equianalgesic doses required for lipophilic drugs?


Because of the highly vascular and adipose-filled nature of the epidural space, a significant amount of lipophilic drug is absorbed by both blood and fat. This serves to reduce the amount of drug “available” to reach the dorsal horn.



11. What factors determine duration of action of spinal opioids?


Termination of action is accomplished after the opioid diffuses away from the receptor and returns to the CSF or is carried away from the spinal cord by venous return. Affinity for the receptor and lipophilicity determine the duration of action. To date, the role for intraspinal metabolism is unclear.



12. What are the common side effects of intraspinal opioids?


Classically, intraspinal opioid side effects are similar to those observed with systemic administration: respiratory depression, urinary retention, pruritus, and nausea and vomiting. Tolerance and physical dependence may also occur.



13. Which is the most common side effect?


Pruritus has been shown to occur quite commonly with intraspinal opioids; however, according to studies by Reiz and Westburg and by Bromage, Camporesi, and Chestnut, the incidence is highly variable: 15% to 100%. The exact mechanism is unknown, but probably does not involve histamine release. Pruritus responds to low-dose intravenous naloxone (5 mg/kg/hr) without decreasing analgesic effectiveness.



14. How common is urinary retention when using intraspinal opioids?


The incidence of urinary retention when using intraspinal opioids varies between 10% and 50% and does not differ from that of systemically administered narcotics, although the onset and severity may differ (see Stenseth and Breirik). Reducing the administered dose does not decrease the incidence. The mechanism of action involves inhibition of the volume-evoked micturition reflex. Urinary retention responds to low-dose naloxone.

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Jun 14, 2016 | Posted by in PAIN MEDICINE | Comments Off on Intraspinal Opioids

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