Analgesia

• In 1973, opioid receptors were discovered in the brain and spinal cord by Pert and Snyder.2

• In 1976, animal studies demonstrated powerful and selective analgesic effects of intrathecal opioids.3

• In 1979, Behar et al.4 demonstrated that the epidural administration of a 2 mg dose of morphine produced profound analgesia.

• In 1979, Wang et al.5 demonstrated the profound analgesic effect of intrathecal opioids.

It has been shown that the analgesic effect of opioids delivered to the epidural or intrathecal space is mainly due to the drug being taken up directly into the spinal cord and cerebrospinal fluid.6 By delivering analgesic drugs directly to the spinal cord and cerebrospinal fluid, a selective concentration of the drug is allowed to act at an important site of pain transmission, the dorsal horn of the spinal cord.

Spinal administration can therefore be extremely effective in terms of analgesia and further, it can overcome unwanted motor, sensory, and autonomic effects from the systemic administration of what are inevitably larger doses of drugs (Figure 21.1).

Figure 21.1 Greater analgesia with fewer side effects through spinal drug delivery.

The term selective spinal analgesia, originally used by Cousins et al.7 in 1979, has come into common usage. The drugs most commonly used for spinal administration are opioids. Spinal administration can be the route of delivery of other drugs and can enable patients to be exposed to drugs that are unstable by nonspinal routes of administration. Other drugs which are delivered by spinal administration are local anesthetics, clonidine (an alpha-2 adrenergic agonist), and more recently ziconotide. Intra-thecal baclofen is used to treat severe spasticity, which in turn has an impact on the pain of spasticity and the pain caused by deformities and disabilities of spasticity. There are reports of the use of other drugs, but there is no high quality evidence for these.

It is recognized that single shot spinal doses are only appropriate in the acute perioperative setting. The use of the techniques in the management of ongoing pain requires systems for the continuous delivery of drugs.

Figure 21.2 Differences between (a) normal and (b) brain capillaries.

The blood-brain barrier

For systemic medications to reach tissues they must cross the endothelial lining of capillaries. These differ in different organs and relevant to this discussion is the lack of fenestrations of central nervous system endothelial cells acting as a barrier to drug passage (Figure 21.2). This is clearly a teleological protection mechanism from neuro-toxins but hampers therapeutic drug delivery by the systemic route (Figure 21.3, indicator 3). It can be overcome by direct administration into the cerebrospinal fluid (indicator 2).

Central nervous system blood flow

The vast majority of central nervous system blood flow is to the more metabolically active brain when compared with the spinal cord (Figure 21.4).

As a result, systemic drugs that are distributed as a function of blood flow lead to a much greater delivery to the brain than spinal cord. Whilst both are important sites of analgesia, they have a differing spectrum of nonanalgesic (side) effects, with more derived from the brain. Again, direct spinal cerebrospinal fluid administration can overcome this.

Spasticity

In normality, muscle tone is maintained by constant activity from alpha neurones whose cell bodies are located in the anterior horn of the spinal cord. If the stretch receptors within muscle indicate lengthening of the muscle then the muscle contracts. The threshold at which the stretch receptor fires is controlled by gamma neurones. In pathophysiological states there is a failure of

GABA-mediated inhibition of alpha neurones and an imbalance between active and passive muscles results. Baclofen (a GABA-B agonist) corrects this.

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