Opioids are commonly used as part of an intrathecal (IT) mixture of agents for treatment or prevention of peri-operative pain. They can be used as an analgesic adjunct (e.g. spinal and general anaesthetic for endovascular aneurysm repair) or as a sole anaesthetic technique (e.g. epidural for hip arthroplasty). Their use was first explored in the 1970s, when opioid receptors were identified in the dorsal horn of the spinal cord (1977) and opioids were noted to modulate the response to nociceptive stimuli via direct action on the spinal cord (1976). Morphine was the first opioid used as an intrathecal agent, in 1979.
Proposed mechanism of action
Pre- and postsynaptic receptors were identified in laminae I and II of the dorsal horn. All are G protein-linked receptors which activate ion channels when opioids bind to them, via a conformational change.
- Mu opioid (MOP) receptors/delta opioid (DOP) receptors --> K+ channels open
- Kappa opioid (KOP) receptors --> Ca2+ channels close
The net effect is reduced Ca2+ influx with a subsequent reduction in the release of glutamate and substance P from presynaptic C fibres but not A fibres. This produces an overall reduction in nociceptive transmission.
Other proposed actions include:
- An increased concentration of adenosine has been found in the cerebrospinal fluid (CSF) after intrathecal (IT) morphine is administered. Adenosine is known to hyperpolarise neurones by increasing K+ influx.
- A reduction in gamma-aminobutyric acid (GABA) and glycine concentrations is found after IT opioids. This reduces the inhibition of inhibitory pathways, allowing them to modulate nociceptive stimuli.
Ideal IT opioid
The spinal cord and neurones are mainly lipid-rich tissues which are bathed in CSF. Therefore, an opioid delivered into the IT space must diffuse from the CSF (hydrophilic) into the neuronal tissues (lipophilic) to reach its site of action. Ideal IT opioids would have a rapid, predictable effect with a limited duration of action, to reduce the potential side effects of IT opioids.
Features which encourage this are high lipid solubility and low pKa. This ensures rapid uptake from the CSF into the neuronal tissue; molecules that are more hydrophobic have a higher potency via the IT route compared with when administered intravenously. Parenteral opioid potency cannot be translated to IT potency.
Morphine (pKA 7.9) is highly soluble in the CSF and less absorbed into the neuronal tissue, giving a slow onset of action. This causes higher concentrations in the CSF and long cord exposure times up to 12 hours post-administration. It binds well to dorsal horn receptor sites but not others in the myelin and white matter of the spinal cord. There is a higher histamine release, resulting in pruritus. The Procedure-Specific Postoperative Pain Management (PROSPECT) trial recommended IT morphine at 0.1–0.2 mg for hip arthroplasty.
Diamorphine (pKa 7.6) is a prodrug with highly lipophilic properties, and its fast metabolism into morphine results in a rapid onset of action. Once metabolised to morphine, it becomes more water soluble and is excreted via the plasma, giving it a shorter duration of action. A similar histamine release profile to that of morphine results in pruritus. NICE recommends use of IT diamorphine for analgesia in Caesarean section (CG 132).
Fentanyl (pKa 8.4) is highly lipophilic. When administered via the IT route, its onset of action is faster than that of diamorphine but has a prolonged duration of action and can result in late-onset side effects. There is limited cephalad spread with segmental analgesia and a lower incidence of pruritus. NICE recommends the use of fentanyl as the opioid of choice for labour epidurals, in combination with low-concentration bupivacaine (CG 190).
Distribution and removal of IT opioids
Once delivered via the IT route in the lumbar region, opioid molecules move in a cephalad direction owing to:
- Bulk CSF flow from caudal to cephalad regions
- Pressure changes in the thorax, which act as an additional pump effect in a cephalad direction
- The cardiac cycle causing minor expansion and relaxation changes in the brain tissue, resulting in net cephalad movement of CSF.
The fate of IT opioids in the CSF is diffusion from this hydrophilic space into the hydrophobic tissues surrounding the neurones. This can either be the spinal cord or the epidural fat; the latter can be a store of opioids and release them slowly over a period of time. Once in the lipid-rich tissues, the concentration gradient eventually drives diffusion back into the plasma via spinal or epidural blood vessels, and removal from the CNS.
Side effects of IT opioids
- Sedation – alters electroencephalogram and reduces minimum alveolar concentration for anaesthesia
- Respiratory depression – reduces sensitivity to CO2 via medullary receptors
- Suppress upper airway receptors
- Hypotension and bradycardia – due to loss of sympathetic tone and high block
- Pruritus – histamine-mediated, treated with low-dose naloxone incrementally, ondansetron and chlorphenamine
- Nausea and vomiting – direct stimulation of chemoreceptor trigger zone
- Delayed gastric emptying – increased gastrointestinal muscle tone and reduced motility
- Urinary retention
Author: Dr Emma Bryden
Hindle A. Intrathecal opioids in the management of acute postoperative pain. Contin Educ Anaesth Crit Care Pain 2008; 8(3): 81–85.