Morphine is an opioid 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. Administration may be as a bolus, an infusion, or a combination of the two. Intrathecally administered morphine must be preservative-free, sterile, nonpyrogenic, and free of antioxidants and other potentially neurotoxic additives. A filter needle is necessary 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 intrathecal requires close attention to dosing as the potency of the morphine is dramatically enhanced by intrathecal delivery. The recommended bolus dose for intraoperative and postoperative analgesia is 0.1 to 0.2 mg intrathecally. The recommended starting dose of intrathecal morphine continuous infusion is 0.1 to 1.0 mg per day in patients without tolerance to opioids and variable dosing in those with tolerance to high doses of oral agents [1][2].  Compare these doses with the much larger 1-4 mg of morphine that would be given intravenously to an opioid-naive patient. 

Clinical Uses of Intrathecal Morphine

• Labor analgesia
• Perioperative analgesia for intra-abdominal, intra-thoracic, and orthopedic surgery of the lower extremities
• Perioperative analgesia for Cesarean section
• Severe chronic pain in patients who have not obtained adequate analgesia from more conservative therapies

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. One benefit of intrathecal delivery is since it bypasses first-pass metabolism and the blood-brain barrier by working directly at the dorsal horn of the spinal cord, morphine can achieve an analgesic effect at a lower dose and with potentially less systemic side effects than with large dose oral opioids [1]. 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 pulmonary disease, obstructive sleep apnea, or substance abuse. Intrathecal administration of morphine through implantable pumps should be avoided in patients with cancer-related pain with life expectancy less than 3 months as it takes time to titrate optimal dosing regimen [3][4].

Opioids work in three distinct areas of the central nervous system (CNS): the periaqueductal-periventricular gray matter, the ventromedial medulla, and the spinal cord. [5] Morphine interacts predominantly with the mu-receptor. The mu-binding sites of opioids are present 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 on the terminal axons of primary afferents within the substantia gelatinosa of the spinal cord.[6][7]

Pharmacodynamics/Kinetics

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.

Adverse Reactions

• Respiratory depression or arrest (dose-dependent)
• Nausea and/or vomiting
• Hypotension
• Bradycardia
• Pruritis
• Dependency
• Miosis
• A headache
• Seizures
• Urinary retention
• Granuloma formation at end of intrathecal catheter [1]

Pregnancy

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 local anesthetic (such as bupivacaine) in spinal anesthesia during Cesarean section.

Drug Interactions

Intrathecal morphine may potentiate other medications that cause CNS or respiratory depression and cardiovascular depression.  It lowers the seizure threshold and requires caution for use 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 use also requires 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 use requires 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 use also requires 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 subject to close monitoring.