Intrathecal Morphine


Article Author:
Adrienne Cummings


Article Editor:
Brian Fitzgerald


Editors In Chief:
Sherri Murrell


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Nazia Sadiq
Hajira Basit
Phillip Hynes
Komal Shaheen
Sandeep Sekhon


Updated:
10/12/2019 11:31:26 AM

Indications

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 is essentially a dose-escalation because the potency of the medication gets dramatically enhanced by intrathecal delivery. The recommended bolus dose for intraoperative and postoperative analgesia is 0.1 to 0.2 mg. 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].

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.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 pumps should be avoided in patients with cancer-related pain with life expectancy less than 3 months.[3][4]

Mechanism of Action

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]

Administration

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 Effects

Adverse Reactions

  • Respiratory depression or arrest (dose-dependent)
  • Nausea and/or vomiting
  • Hypotension
  • Bradycardia
  • Pruritis
  • Dependency
  • Miosis
  • A headache
  • Seizures
  • Urinary retention

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 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

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.

Monitoring

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 the level of consciousness requires vigilant monitoring.

Cardiovascular Effects

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.

Respiratory Effects

The single most serious adverse event encountered during the 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. Clinicians should limit additional opioids for the first 24 hours after administration.  If necessary, the patient should be monitored closely for signs of respiratory depression/apnea.

Toxicity

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.

Enhancing Healthcare Team Outcomes

Intrathecal morphine is usually only administered by an oncologist, anesthesiologist, or a pain specialist. 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. 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 pumps should be avoided in patients with cancer-related pain and life expectancy less than three months. Patients with intrathecal morphine pumps need to be monitored by the nurse. The nurse should always have an order for naloxone in case the patient shows signs of opioid toxicity.[1]

The use of intrathecal morphine requires an interprofessional healthcare team. The clinician(including pain specialists or oncologist) will initiate treatment with intrathecal morphine, but a pharmacist should also have involvement to verify appropriate dosing, and should also check for potential drug interactions (e.g., CYP3A4 agonists/antagonists). Nursing will be administering the drug and should understand proper administration and dosing, as well as the signs of toxicity and report any concerns to the clinician promptly. This type of interprofessional team approach optimizes intrathecal morphine administration, results, and safety, leading to better patient outcomes for pain control. [Level V]


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Intrathecal Morphine - Questions

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A postoperative patient has received intrathecal morphine. Which of the following is appropriate?



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You are about to asked to administer intrathecal narcotics for a patient with pancreatic cancer. Compared to intravenous dosing, when administering morphine in the intrathecal space, which is correct?



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A 32-year-old female scheduled to undergo elective Cesarean section. She has a history of depression, seizure disorder, chronic supraventricular tachycardia, and extreme obesity. Which of the following is not a consideration for the avoidance of intrathecal morphine in her subarachnoid space.



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You are called by the floor to evaluate a 52-year-old patient with severe respiratory depression 8 hours after a hip hemiarthroplasty. The patient received 10mg oxycodone, 1 g acetaminophen, 200mg celecoxib pre-operatively. His primary anesthetic was a subarachnoid block with 1.5mg isobaric bupivacaine, 200 mcg morphine, and 20 mcg fentanyl. The patient received 50 mcg fentanyl 2 hours ago and a dose of ketorolac 30 minutes ago. What is the most likely cause of his respiratory depression?



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You are called to evaluate a patient on the postpartum ward who has become unresponsive to verbal and physical stimulation status post elective Cesarean section. The patient received a subarachnoid block with 12 mg hyperbaric bupivacaine, 25 mcg fentanyl, and 300 mcg morphine. Additionally, she received 2mg midazolam for periprocedural anxiety and 4mg intravenous (IV) morphine in the post-op phase for breakthrough pain. The ward nurse reports that the patient received 30 mg IV ketorolac and two tabs of oxycodone and acetaminophen 45 min ago for pain. Over the last 10 to 15 minutes the patient has become more lethargic and now is no longer answering questions. Heart rate is 60 bpm, blood pressure 140/80 mmHg, respiratory rate 6/minute, and pulse oximetry 96% on 2L by nasal cannula. Which immediate action is most likely to improve the patient's mental status?



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Intrathecal Morphine - References

References

Grass JA, Fentanyl: clinical use as postoperative analgesic--epidural/intrathecal route. Journal of pain and symptom management. 1992 Oct;     [PubMed]
Deer TR,Pope JE,Hanes MC,McDowell GC 2nd, Intrathecal Therapy for Chronic Pain: A Review of Morphine and Ziconotide as Firstline Options. Pain medicine (Malden, Mass.). 2018 Aug 22;     [PubMed]
Xing F,Yong RJ,Kaye AD,Urman RD, Intrathecal Drug Delivery and Spinal Cord Stimulation for the Treatment of Cancer Pain. Current pain and headache reports. 2018 Feb 5;     [PubMed]
Hutchins JL,Renfro L,Orza F,Honl C,Navare S,Berg AA, The addition of intrathecal morphine to a transversus abdominis plane block with liposome bupivacaine provides more effective analgesia than transversus abdominis plane block with liposome bupivacaine alone: a retrospective study. Local and regional anesthesia. 2019;     [PubMed]
Shah N,Padalia D, Intrathecal Delivery System 2019 Jan;     [PubMed]
Raft J,Podrez K,Baumann C,Richebé P,Bouaziz H, Postoperative clinical monitoring after morphine administration: a retrospective multicenter practice survey. Current drug safety. 2019 Mar 5;     [PubMed]
Kjølhede P,Bergdahl O,Borendal Wodlin N,Nilsson L, Effect of intrathecal morphine and epidural analgesia on postoperative recovery after abdominal surgery for gynecologic malignancy: an open-label randomised trial. BMJ open. 2019 Mar 4;     [PubMed]

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