Morphine is an opioid that is administered for acute and chronic pain conditions. The advantage of intrathecal (IT) morphine over intravenous (IV), oral (PO) or transdermal (TD) opiates is due to its delivery into the subarachnoid space with direct access to opiate receptors and ion channels. It may be administered as a bolus, an infusion, or a combination of the 2. Morphine that is administered intrathecally must be preservative free, sterile, nonpyrogenic, and free of antioxidants and other potentially neurotoxic additives. A filter needle should be used when drawing up intrathecal morphine from a glass vial as small glass particles can be catastrophic to neural tissue when administered into the intrathecal space.
Changing the route of morphine administration from systemic to IT is essentially a dose escalation because the potency of the medication is dramatically enhanced by IT delivery. The recommended bolus dose for intraoperative and postoperative analgesia is 0.1 to 0.2 mg. The recommended starting dose of IT morphine continuous infusion is 0.1 to 1.0 mg per day in patients without tolerance to opioids and variable dosing in those with a tolerance to high doses of oral agents.
Clinical Uses of Intrathecal Morphine
Typically, intrathecal morphine is more likely to benefit patients with nociceptive or neuropathic pain that is well localized and responsive to systemic opioids. This pain may or may not be cancer-related.Intrathecal morphine is less likely to benefit patients with pain that is refractory to systemic opioids. Additionally, intrathecal opiates should be avoided or minimized in patients with substance abuse, pulmonary disease, obstructive sleep apnea or substance abuse. Intrathecal administration of morphine through implantable pump should be avoided in patients with cancer-related pain with life expectancy less than 3 months.
Opioids work in 3 distinct areas of the central nervous system (CNS): the periaqueductal-periventricular gray matter, the ventromedial medulla, and the spinal cord. Morphine interacts predominantly with the mu-receptor. The mu-binding sites of opioids are distributed in the brain, with high densities of sites found in the posterior amygdala, hypothalamus, thalamus, caudate nucleus, putamen, and some cortical areas. They are also found on the terminal axons of primary afferents within the substantia gelatinosa of the spinal cord.
Route of Administration: Intrathecal
The onset of action: 5 to 10 minutes
Duration of action: Clinical duration of action can be as long as 20 hours given the biphasic pattern
Distribution: 1.0 to 4.7 L/kg after intravenous dosing. Limited data suggest that the volume of distribution of morphine in the intrathecal space is 22+/- 8 mL.
Protein Binding: 36% (low)
Metabolism: Hepatic glucuronidation to morphine-3-glucuronide, which pharmacologically inactive
Half-life: The disposition of morphine in the cerebrospinal fluid (CSF) follows a biphasic pattern with an early half-life of 1.5 hours and a late phase half-life of about 6 hours
Excretion: Primarily renal excretion of the conjugate (morphine-3-glucuronide). Approximately 2% to 12% is excreted unchanged in the urine
The risks/benefits of intrathecal morphine should be considered during pregnancy, especially if prolonged use. The risk of teratogenicity is low. During labor and delivery, there is a risk for respiratory depression in both the mother and neonate. Respiratory depression, bradycardia, and withdrawal are all possible in the neonate with prolonged morphine exposure. It is routinely used as an analgesic in combination with spinal anesthesia during Cesarean section.
Intrathecal morphine may potentiate other medications that cause CNS or respiratory depression and cardiovascular depression. It lowers the seizure threshold and should be used with caution in patients predisposed to seizure. Intrathecal morphine also has a weak serotonergic effect and should be used with caution in patients on SSRIs. Intrathecal morphine is a CYP3A4 substrate and should be used with caution in patients on other medications affecting the CYP3A4 enzyme.
Contraindications to intrathecal morphine are the same as for intravenous morphine and include allergy to morphine or other opiates, acute bronchial asthma, upper airway obstruction, severe hypovolemia or other etiology of severe hypotension.
Intrathecal morphine should be used with extreme caution in patients with head injury or increased intracranial pressure. Pupillary changes (miosis) from intrathecal morphine may interfere with the diagnosis and monitoring of intracranial pathology. Hypercarbia from respiratory depression may worsen intracranial hypertension. High doses of neuraxial morphine may produce myoclonic events which may interfere with the assessment of intracranial pathology.
Intrathecal morphine should be used with caution in patients who have decreased respiratory reserve (chronic-obstructive pulmonary disease [COPD], severe obesity, kyphoscoliosis, phrenic nerve palsy, muscular dystrophies, among others) as acute respiratory failure is possible following administration of intrathecal morphine.
Elimination half-life may be prolonged in patients with reduced metabolic rates and with hepatic or renal dysfunction. High blood morphine levels due to reduced clearance may take days to develop so patients should be monitored closely.
Therapeutic Effects of Intrathecal Morphine
When administered intrathecally, morphine has a rapid and smooth onset that is variable in its duration.
Central Nervous System Effects
Intrathecal morphine causes miosis and can lower the seizure threshold. It can lead to CNS depression, and level of consciousness should be monitored closely.
A single dose of intrathecal morphine can lead to orthostatic hypotension in patients with intravascular hypovolemia or impaired myocardial function on sympatholytic drugs. Intrathecal morphine can lead to bradycardia that may potentiate hypotension further.
The single most serious adverse event encountered during administration of intrathecal morphine is respiratory depression or respiratory arrest. Intrathecal morphine can lead to severe respiratory depression that can last up to 24 hours following administration and could lead to respiratory arrest. This respiratory depression follows a biphasic pattern with initial onset within the first 1 to 3 hours and a late onset at about 6 to 12 hours after administration. Additional narcotics should be limited within the first 24 hours after administration. If necessary, the patient should be monitored closely for signs of respiratory depression/apnea.
Naloxone, the antidote for an overdose of opiates, is a competitive mu opioid–receptor antagonist that reverses all signs of opioid intoxication. It can be given parenterally, intranasally or via an endotracheal tube. The initial dose of overdose is 0.04 mg which can be increased every 2 minutes to a maximum of 15 mg. The onset of action is generally less than 2 minutes when given intravenously. Duration of action is 20 to 90 minutes which is shorter than the opiate effects often rendering redosing or infusion necessary. A trial has shown that a dose of 0.4 mg followed by a 0.4 to 0.6 mg per hour IV provided at least 50% pain relief in 78% of patients with a significantly decreased incidence of pruritus during labor and delivery. There was no significant decrease in the incidence of nausea, vomiting, somnolence, dizziness or urinary retention in patients given this dose of naloxone.