Continuing Education Activity

Morphine serves as a cornerstone in the management of moderate to severe pain, whether acute or chronic, with particular utility in palliative care, oncology settings, and vaso-occlusive crises associated with sickle cell disease. This activity provides healthcare professionals with essential knowledge regarding the FDA-approved indications for morphine and a thorough review of the drug’s mechanism of action, pharmacokinetics, and key contraindications. Information on administration techniques, potential drug interactions, and adverse effects, including those highlighted in FDA-issued warnings, supports informed clinical decision-making.

A clear understanding of morphine’s pharmacological properties allows clinicians to tailor treatment strategies that align with individual patient needs while minimizing the risk of adverse outcomes. This activity highlights evidence-based practices for managing pain safely and effectively using morphine across diverse care settings. Special attention is given to the role of the interprofessional healthcare team in monitoring therapy, adjusting dosing, and ensuring optimal patient safety.

Objectives:

• Evaluate the mechanism of action of morphine.

• Identify the FDA-approved indications and off-label uses for morphine.

• Assess the contraindications and adverse events associated with morphine administration.

• Implement effective collaboration and communication among interprofessional team members to improve the outcomes and treatment efficacy of morphine therapy for patients who might benefit from it.

Indications

FDA-Approved Indications

FDA-approved usage of morphine includes moderate to severe pain that may be acute or chronic. Most commonly used in pain management, morphine provides significant relief to patients afflicted with pain.[1] Clinical situations that benefit significantly from medicating with morphine include management of palliative/end-of-life care, active cancer treatment, and vaso-occlusive pain during sickle cell crisis. Morphine is FDA-approved for the management of both acute and chronic pain when alternative therapies are insufficient. Injectable morphine is indicated for severe pain that requires opioid analgesia and when other treatment options are inadequate. This formulation is also approved for epidural or intrathecal administration, though it should not be used in continuous microinfusion devices. Different formulations of morphine are approved explicitly for continuous microinfusion in epidural or intrathecal settings, offering a solution for managing intractable chronic pain in patients who require an opioid and have not responded to less invasive pain management methods. Extended-release oral formulations are indicated for managing severe and persistent pain that necessitates daily opioid treatment over an extended period when alternative therapies are ineffective. Immediate-release oral formulations, including solutions and tablets, are used to manage acute pain (for pediatric patients aged 2 years and older) and chronic pain (adults) when opioid analgesia is required, and other treatments have proven inadequate. Rectal formulations of morphine are also approved for managing both acute and chronic pain under similar conditions, offering another route of administration when necessary.

According to the Centers for Disease Control and Prevention (CDC) guidelines, clinicians should not use extended-release/long-acting (ER/LA) opioids, including morphine, to treat acute pain or initiate opioid treatment for subacute or chronic pain. Due to their longer half-life and extended duration of effects, such as respiratory depression, ER/LA opioids should be reserved for severe continuous pain. When switching to an ER/LA opioid, clinicians should reduce the total daily dosage to account for incomplete opioid cross-tolerance.[2] According to the American Society of Clinical Oncology (ASCO) guidelines, healthcare institutions should have access to immediate-release (IR) oral and injectable morphine to address the pain management needs of patients with cancer. These medications should be prescribed and dispensed by appropriately trained healthcare providers. Additionally, in limited-resource settings, access to both immediate-release and sustained-release morphine, along with injectable morphine, should be ensured. This recommendation guarantees that these 3 forms of morphine are accessible at both the basic and limited-resource levels for cancer pain management.[3]

Off-Label Uses

Morphine is commonly used off-label for almost any condition that causes severe pain. In the emergency department, morphine is given for musculoskeletal pain, abdominal pain, chest pain, and even headaches when patients fail to respond to first and second-line agents.[4] Morphine is rarely used for procedural sedation. However, for minor procedures, physicians will sometimes combine a low dose of morphine with a low dose of benzodiazepine-like lorazepam. Patients who are actively having acute coronary syndrome are often given morphine in the emergency setting before going to the cath lab. Morphine to relieve pain during a myocardial infarction (MI) has been in use since the early 1900s. An observational study conducted in 2005 raised some concerns, but few effective alternatives exist. Morphine is a potent opioid; it decreases pain, which in turn leads to a decrease in the activation of the autonomic nervous system. These are desirable effects when a patient is having an MI. Additionally, morphine has hemodynamic side effects that can be beneficial during an MI.[5] Morphine can reduce heart rate, blood pressure, and venous return. Morphine can also stimulate local histamine-mediated processes.[6] In theory, the combination of these can reduce myocardial oxygen demand.

According to the American College of Cardiology (ACC) and American Heart Association (AHA) STEMI guidelines, morphine sulfate is recommended for pain relief in patients with STEMI, particularly those with complications like acute pulmonary edema. This medication helps reduce breathing difficulty and anxiety and improves ventricular loading. Non-steroidal anti-inflammatory drugs (NSAIDs), except aspirin, are contraindicated in STEMI due to an increased risk of death, reinfarction, hypertension, renal insufficiency, and heart failure.[7] For adults and children with sickle cell disease who have emerging or recently developed chronic pain, the American Society of Hematology guideline panel suggests against starting chronic opioid therapy unless the pain does not respond to several other treatment options.[8]

Mechanism of Action

Morphine is considered the classic opioid analgesic with which other painkillers are compared. Like other medications in this class, morphine has an affinity for delta (δ), kappa (κ), and mu (μ)-opioid receptors.[9] This drug produces most analgesic effects by binding to the μ-opioid receptor within the central nervous system (CNS) and the peripheral nervous system (PNS).[10] The net effect of morphine is the activation of descending inhibitory pathways of the CNS as well as inhibition of the nociceptive afferent neurons of the PNS, which leads to an overall reduction of nociceptive transmission. Opioid receptors are key players in pain modulation in the central nervous system (CNS), mediating functions such as pain relief and euphoria. While opioids like morphine and heroin are potent painkillers, they also carry risks of addiction, tolerance, and dependence. Their activation triggers the G-protein-coupled receptor (GPCR) signaling cascade via G_i and G₀ proteins. The intracellular complex has 3 subunits: alpha (α), beta (β), and gamma (γ). Upon stimulation, these receptors primarily trigger 2 signaling pathways: the β-arrestin and G-protein pathways, with varying preferences depending on the receptor subtype. The β-arrestin pathway is involved in receptor desensitization and internalization.[11]

Pharmacokinetics

Absorption: Morphine is absorbed from the gastrointestinal tract, with peak analgesic effects occurring about 60 minutes after administration. However, its oral bioavailability is less than 40% due to significant first-pass metabolism in the liver. Intrathecal morphine, in contrast, bypasses first-pass metabolism, directly entering the cerebrospinal fluid with slow absorption from the spinal cord into the systemic circulation, ensuring prolonged analgesia.

Distribution: Systemic morphine is widely distributed to tissues, including the liver, kidneys, intestines, lungs, and skeletal muscles. Morphine crosses the blood-brain barrier but in limited amounts due to its low lipophilicity. Morphine also crosses the placental barrier and is excreted in breast milk.[12] The volume of distribution ranges from 1 to 6 L/kg, with 20% to 35% reversibly bound to plasma proteins. Intrathecal morphine binds effectively to spinal receptors, concentrating analgesic effects in the spinal cord while minimizing systemic redistribution. The intrathecal route ensures sustained action within the spinal cord, with delayed systemic effects such as respiratory depression, typically manifesting 6 to 12 hours post-administration.[13]

Metabolism: Morphine undergoes extensive hepatic metabolism and is primarily metabolized orally through conjugation with D-glucuronic acid to form morphine-3-glucuronide and morphine-6-glucuronide. The morphine-6-glucuronide metabolite has analgesic activity but poor blood-brain barrier penetration, while morphine-3-glucuronide has no significant analgesic effect. A small fraction undergoes demethylation.

Elimination: Morphine is excreted in urine as glucuronide metabolites, with approximately 10% excreted unchanged. Some metabolites are excreted in bile, where minor enterohepatic recycling occurs. The plasma clearance of morphine is around 20 to 30 mL/min/kg. After intravenous administration, its terminal half-life is typically 2 hours. Extended-release formulations, such as extended-release epidural morphine, use liposomal encapsulation to delay peak concentration in the cerebrospinal fluid (CSF), providing up to 48 hours of analgesia with a single dose.[14]

Administration

Available Dosage Forms

Morphine administration most often occurs via the following routes: orally (PO), intravenously (IV), epidural, and intrathecal. Oral formulations are available in immediate and extended-release for treating acute and chronic pain. Pain that is more severe and not well controlled may be manageable with single or continuous doses of IV, epidural, and intrathecal formulations.[4] Infusion dosing can vary significantly between patients and largely depends on how naive or tolerant they are to opiates. IV morphine formulation is also commonly given intramuscularly (IM). Morphine is also available as a suppository.[15] Morphine is widely used and abused. As a result, people have found ways to insufflate (snort) the medication.[16] Morphine is also available as an oral solution and can be administered sublingually. Sublingual morphine is very popular in palliative care.

Available Strengths

Morphine is available in various formulations and strengths for different therapeutic uses. These include immediate-release tablets in strengths of 15 mg and 30 mg and extended-release tablets available in 15 mg, 30 mg, 60 mg, 100 mg, and 200 mg doses. Extended-release capsules are also available in multiple strengths, including 10 mg, 20 mg, 30 mg, 45 mg, 50 mg, 60 mg, 75 mg, 80 mg, 90 mg, 100 mg, 120 mg, and higher dosages up to 200 mg. Additionally, injectable solutions of morphine sulfate are offered in concentrations such as 0.5 mg/mL, 1 mg/mL, 2 mg/mL, 4 mg/mL, 5 mg/mL, 8 mg/mL, 10 mg/mL, 15 mg/mL, 25 mg/mL, and 50 mg/mL. Higher-potency injectable forms with concentrations such as 10 mg/mL and 25 mg/mL are also available. Morphine sulfate is also available as suppositories in doses of 5 mg, 10 mg, 20 mg, and 30 mg, and as an oral solution in concentrations of 10 mg/5 mL, 20 mg/5 mL, and 20 mg/mL.

Adult Dosage

According to product labeling, the starting dose of intravenous morphine for adults should range from 2 mg to 10 mg per 70 kg of body weight, with the lowest effective dose used to achieve adequate pain relief. Dosage should be titrated based on the patient's response to the initial dose of preservative-free morphine sulfate injection. When administered epidurally, an initial dose of 5 mg in the lumbar region may provide effective pain relief for up to 24 hours. If adequate relief is not obtained within an hour, incremental 1 to 2 mg doses may be given at intervals to assess efficacy. However, the total should not exceed 10 mg in 24 hours.

For intrathecal administration, the typical dose is approximately one-tenth of the epidural dose, with a single dose of 0.2 to 1 mg offering relief for up to 24 hours. For opioid-naive adults, the initial oral morphine dose is 15 mg to 30 mg every 4 hours as needed, adjusted to achieve adequate pain relief. For pediatric patients weighing at least 50 kg, start with 15 mg every 4 hours, with a maximum initial dose of 30 mg. When converting from parenteral morphine, 3 to 6 mg of oral morphine is equivalent to 1 mg of parenteral morphine. Conversion to extended-release morphine requires caution as it can lead to increased sedation and respiratory depression due to slower release. Dosages should be titrated individually to balance pain relief with adverse effects. Patients should be evaluated regularly and the dosage adjusted if pain increases or adverse effects occur. For opioid-naive patients, initiate morphine sustained-release at 15 mg orally every 8 or 12 hours. For opioid non-tolerant patients, start with 15 mg orally every 12 hours. When converting from other oral morphine formulations, administer half of the patient's 24-hour dose as morphine sulfate controlled-release on a 12-hour schedule or one-third on an 8-hour schedule. For conversion from other opioids, discontinue all opioids except as needed for breakthrough pain. Conversion from methadone requires close monitoring due to its long half-life, which may lead to accumulation. Dosage adjustments can be made every 1 to 2 days to balance pain management and adverse effects.

According to a study, intrathecal morphine provides adequate analgesia following lower limb arthroplasty, with a dose of 100 µg optimizing pain relief while minimizing the risk of postoperative nausea and vomiting. However, the increased adverse effect profile, including pruritus and urinary retention, underscores the importance of careful dose selection and multimodal analgesia to balance efficacy and safety.[17] Increasing opioid dosages beyond 50 MME daily offers diminishing benefits for pain and function compared to the associated risks. Clinicians should assess each case individually, considering factors like diagnosis, previous dosage adjustments, treatment effectiveness, and patient preferences. In some states, such as Washington, clinicians must consult a pain specialist before increasing dosages above 120 MME daily. Clinicians should be aware of state-specific policies regarding MME thresholds and related protocols.[2] The dosage for sickle cell disease in adults immediate release oral formulation is 15 mg Q2 to 4h as needed, and in children, 0.2 to 0.5 mg/kg/dose Q2 to 4 hours as required; initial maximum dose: 15 to 20 mg. For intravenous (IV) morphine, the intermittent bolus dosing for adults and pediatrics is 0.1–0.2 mg/kg every 2 to 4 hours as needed, with a maximum dose of 10 mg. For basal infusion, the initial dose for patients weighing less than 50 kg is 0.01 mg/kg/hr, with a dosage range of 0.01 to 0.04 mg/kg/hr. The dosage range for patients weighing 50 kg or more is 1 to 2 mg/hr.[18] In patients with acute coronary syndrome who have persistent symptoms despite antianginal treatment, intravenous morphine may be administered at a dose of 1 mg to 5 mg IV.[19]

Specific Patient Populations

Hepatic impairment: According to the American Association for the Study of Liver Diseases, opioids like morphine should be avoided in cirrhosis, with hydromorphone or oxycodone considered for patients with advanced cirrhosis.[20] Morphine has an oral bioavailability of 35% (range 15% to 64%), which increases to nearly 100% in patients with severe hepatic impairment such as cirrhosis. The plasma half-life is prolonged in these patients, requiring dose adjustments and reduced frequency of administration of immediate-release formulations. Additionally, morphine can induce spasms of the bile duct and sphincter of Oddi, making it contraindicated in biliary colic. 

Renal impairment: Morphine should generally be avoided in individuals with hepatorenal syndrome due to the increased risk of toxicity from morphine-6-glucuronide accumulation in cases of severe renal impairment.[21] In patients with chronic kidney disease (CKD), the accumulation of both the drug and its metabolites, particularly those excreted by the kidneys, can pose significant risks. Although kidneys play a minimal role in the excretion of morphine, its active metabolites, including morphine-6-glucuronide, may accumulate in cases of renal dysfunction, resulting in prolonged effects and potential toxicity. Despite morphine's primary elimination through the liver, the reduced renal function in patients with CKD increases the risk of overdose or adverse reactions.[22]

Pregnancy considerations: Most women undergoing cesarean delivery in the United States receive neuraxial morphine, the most effective form of postoperative analgesia for this procedure. Current guidelines from the American Society of Anesthesiologists (ASA) and the American Society of Regional Anesthesia and Pain Medicine (ASRA) recommend respiratory monitoring standards that may be overly intensive for healthy obstetric patients receiving a single dose of neuraxial morphine. Limited evidence exists on this population's optimal modality, frequency, and duration of respiratory monitoring. This consensus statement from the Society for Obstetric Anesthesia and Perinatology (SOAP) supports using low-dose neuraxial morphine and multimodal analgesia while advocating for patient risk stratification to adjust monitoring protocols. Emphasis is placed on minimizing unnecessary monitoring in healthy patients and targeting increased vigilance in those at higher risk for respiratory depression.[23]

Breastfeeding considerations: The administration of epidural morphine for postoperative analgesia following cesarean sections leads to minimal concentrations of morphine in breast milk. Conversely, intravenous or oral morphine is associated with higher concentrations in breast milk. Maternal use of morphine does not necessitate the cessation of breastfeeding. Following the establishment of lactation, it is advisable to transition to non-narcotic analgesics and restrict the use of morphine to a duration of 2 to 3 days while closely monitoring the infant. If the infant exhibits symptoms such as excessive sleepiness, difficulty in breastfeeding, respiratory distress, or limpness, immediate consultation with a neonatologist is required. Additionally, the use of ketorolac, ibuprofen, and acetaminophen in a multimodal approach to post-cesarean analgesia may reduce the likelihood of mothers not achieving exclusive breastfeeding compared to the use of patient-controlled intravenous morphine.[12]

Pediatric patients: According to the American Academy of Pediatrics guidelines, clinicians are advised to avoid outpatient tapers when possible, and if used, a structured weaning plan with comprehensive follow-up should be implemented to reduce overall medication use. Both non-pharmacologic and pharmacologic treatment protocols should be in place for opioid-exposed infants, with non-pharmacologic interventions forming the foundation of care. Pharmacologic therapy should be reserved for severe opioid withdrawal syndrome (NOWS), mainly when non-pharmacologic interventions are insufficient. Opioids are the first-line treatment for severe NOWS. Infants requiring pharmacologic therapy should be closely monitored, including pulse oximetry. Naloxone should not be used to treat infants with chronic opioid exposure due to the risk of precipitating rapid withdrawal and potential seizures.[24] The American Academy of Pediatrics guidelines for the management of neonatal opioid withdrawal syndrome led to a reduction in pharmacologic treatment and neonatal intensive care unit admissions for affected infants. These changes highlight the effectiveness of nonpharmacologic approaches in managing neonatal opioid withdrawal syndrome and may inform clinical practices for improved patient outcomes.[25]

Older patients: The 2023 American Geriatrics Society Beers Criteria underscores clinical evidence that associates opioid use with a heightened risk of delirium in older adults; use validated pain assessment tools and multimodal strategies.[26] Morphine is often used in palliative care in older patients and should be administered at the lowest dose possible due to potential adverse effects and age-related decline in renal or hepatic function.[27]

Adverse Effects

Among the more common adverse effects of morphine administration is constipation. This effect occurs via stimulation of μ-opioid receptors on the myenteric plexus, inhibiting gastric emptying and reducing peristalsis. Other common side effects include central nervous system depression, nausea, vomiting, and urinary retention. Respiratory depression is among the more serious adverse reactions of opiate use that is especially important to monitor in the postoperative patient population.[28] Other reported side effects include lightheadedness, sedation, and dizziness. Patients often report nausea and vomiting, which is why morphine is frequently administered with an antiemetic such as ondansetron.[29] Other effects include euphoria, dysphoria, agitation, dry mouth, anorexia, and biliary tract spasms, which is why some physicians will avoid morphine when patients present with right upper quadrant pain and suspect possible biliary tract pathology. Morphine can also affect the cardiovascular system and reportedly can cause flushing, bradycardia, hypotension, and syncope. Patients can experience pruritis, urticaria, edema, and other skin rashes. One meta-analysis indicated that intrathecal morphine significantly increases postoperative nausea and vomiting, urinary retention, and pruritus.[30] Adrenal insufficiency has been reported with prolonged opioid use, typically after more than one month. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and hypotension. Diagnosis should be confirmed with testing, and treatment involves physiologic corticosteroid replacement.[31]

Drug-Drug Interactions

• CNS depressants: Central nervous system depressants, including sedative/hypnotics, general anesthetics, tranquilizers, or alcohol, increase the risk of respiratory depression, hypotension, profound sedation, or coma. Caution should be exercised when using morphine in patients on these agents, and dosing should be adjusted accordingly.

• Muscle relaxants: Morphine has the potential to enhance the neuromuscular blocking effects of skeletal muscle relaxants, which could lead to an increased degree of respiratory depression.

• Mixed agonist/antagonist opioids: The use of mixed agonist/antagonist analgesics, such as pentazocine, nalbuphine, or butorphanol, is not advisable for patients on morphine therapy. These agents may reduce the analgesic effects of morphine or precipitate withdrawal symptoms.

• Cimetidine: Concomitant use of morphine and cimetidine has been reported to cause apnea, confusion, and muscle twitching. Patients should be closely monitored for increased respiratory and central nervous system depression when morphine is co-administered with cimetidine.

• Monoamine oxidase inhibitors: Monoamine oxidase inhibitors (MAOIs) significantly enhance the effects of morphine. Serotonin syndrome has been reported.[32] At least 14 days should elapse after discontinuing MAOIs before beginning treatment with morphine.

• Anticholinergics: The concurrent use of morphine with anticholinergics or other medications with anticholinergic properties may elevate the risk of urinary retention and severe constipation, which can progress to paralytic ileus.[33]

• P-glycoprotein inhibitors: P-glycoprotein inhibitors, such as quinidine, may increase exposure to morphine. Therefore, caution is recommended when morphine is co-administered with these inhibitors.[34]

Contraindications

Morphine is a highly beneficial medication when used appropriately. However, in certain situations, this medication may be strongly contraindicated. Extreme caution is necessary for patients with severe respiratory depression and asthma exacerbation cases since morphine can further decrease the respiratory drive. Additionally, morphine should be avoided in cases of previous hypersensitivity reactions and immediately discontinued in the presence of an active reaction.[35] Caution is also necessary with the concurrent use of monoamine oxidase inhibitors (MAOIs) as these medications have an additive effect with morphine. This combination can then trigger severe hypotension, serotonin syndrome, or increased respiratory depression in patients. GI obstruction is another important contraindication.[1] One contraindication for opioid administration is patients with a history of substance misuse, especially if a patient has had a history of abusing opioids. Although this is a very controversial topic, most clinicians would agree that pain requires management.[36] However, most will agree and acknowledge that there are alternatives to opioid analgesics.

Box Warnings

• Respiratory depression: Single-dose neuraxial morphine administration may lead to acute or prolonged respiratory depression for up to 24 hours. Because of the risk of severe reactions with preservative-free morphine sulfate injection administered via epidural or intrathecal routes, patients must be monitored in a fully equipped facility for at least 24 hours after the initial dose. Severe, life-threatening respiratory depression can occur with the use of preservative-free morphine sulfate injection, especially at the beginning of treatment or following an increase in dosage. Proper dosing and titration are critical to minimize the risk of respiratory depression.

• Opioid use disorder: Morphine carries a risk of opioid addiction, misuse, and abuse, which can lead to overdose or death. Clinicians must consider the risk before prescribing.

• CNS depressants: Concomitant use of opioids with central nervous system depressants such as benzodiazepines, including alcohol, can lead to profound sedation, respiratory depression, coma, and death. This combination should only be prescribed when alternative treatment options are insufficient. 

• Neonatal opioid withdrawal syndrome: Prolonged opioid use during pregnancy increases the risk of neonatal opioid withdrawal syndrome, a life-threatening condition if not identified and treated promptly. Patients requiring extended opioid therapy during pregnancy should be informed of this risk, and management should be arranged with neonatologists.

Warnings and Precautions

• Medication errors (oral solution): Morphine oral solution comes in multiple concentrations. Care must be taken to avoid confusion between milligrams and milliliters, which can result in overdose. Always use the provided calibrated oral syringe to ensure accurate dosing, particularly with the high-concentration formulation.

• Respiratory depression: Morphine can cause severe respiratory depression, especially in older, debilitated patients or those with pre-existing respiratory conditions. Monitoring is critical, and non-opioid analgesics should be considered when appropriate.

• Misuse, abuse, and diversion: As a Schedule II controlled substance, morphine carries a high risk of misuse and diversion. Physicians should assess for risk factors and educate patients on the importance of following prescribed dosages to minimize abuse. According to the CDC, long-term opioid prescriptions (over 90 days) significantly increase the risk of developing a new opioid use disorder. The adjusted odds ratios for the risk were 15 for low doses (1 to 36 MME daily), 29 for medium doses (36 to 120 MME daily), and 122 for high doses (≥120 MME daily), compared to no opioid prescription.[2]

• Head injury and increased intracranial pressure: Morphine may worsen respiratory depression and increase intracranial pressure in patients with head injuries. These effects can mask vital neurological signs, so they should be avoided in such cases.[37]

• Hypotension: Morphine can cause hypotension, especially in patients who are already hemodynamically compromised. Caution is needed in those with low blood pressure or circulatory shock.

• Gastrointestinal effects: Morphine reduces gastrointestinal motility and should not be used in patients with gastrointestinal obstruction or ileus, as it may worsen the condition and obscure the diagnosis of acute abdominal issues.

• Use in pancreatic/biliary tract disease: In patients with biliary tract disease or pancreatitis, morphine can induce sphincter of Oddi spasm and worsen the condition. Once avoided as a treatment for pancreatic diseases due to concerns about the sphincter of Oddi spasm, opioids are now essential for managing severe pain in acute pancreatitis. While no opioid has proven superior, tramadol, oxycodone, and fentanyl are commonly used, with recent evidence suggesting buprenorphine outperforms diclofenac in pain control. More research is required; use with caution.[38]

• Driving and operating machinery: Patients should be warned that morphine may impair their ability to perform activities requiring mental or physical alertness, such as driving or operating machinery, especially when combined with other CNS depressants.

• Child safety: Morphine must be kept out of children's reach. Accidental ingestion can lead to life-threatening consequences, and immediate medical attention is necessary if it occurs.

• Opioid-induced hyperalgesia/allodynia: Opioid-induced hyperalgesia (OIH) occurs when opioid use leads to an increased sensitivity to pain, opposite of the expected analgesic effect. Symptoms may include heightened pain with dose escalation, reduced pain with dose reduction, or pain from non-painful stimuli (allodynia), often without evidence of disease progression or opioid withdrawal. If suspected, consideration should be given to dose reduction or opioid rotation to manage OIH and avoid further complications.[39]

Monitoring

The efficacy and therapeutic index of morphine are assessable with a combination of subjective and objective findings. Controlling pain, which is usually the first symptom evaluated in patients, is the ultimate goal of morphine use. Other essential parameters requiring monitoring include mental status, blood pressure, respiratory drive, and misuse/overuse.[4] Monitoring concomitant medications is vital.[40] This list includes but is not limited to prescription medications. All patients taking morphine should understand the need to avoid any other substances that could lead to respiratory depression.[41] These medications include but are not limited to alcohol, additional opioids, benzodiazepines, and barbiturates. Patients can become apneic at lower doses if combining morphine with any of these substances.

Morphine is considered low-risk for QT interval prolongation. However, patients with preexisting cardiac disorders or congenital long QT syndrome require caution.[42][43] Nociception level monitor (NOL)-oriented monitoring analgesia effectively reduces intraoperative opioid consumption without impacting postoperative nausea and vomiting or post-mastectomy pain. Future large-scale randomized controlled trials are needed to explore long-term benefits, especially regarding opioid optimization in breast cancer surgery.[44] Physicians and pharmacists should check prescription drug monitoring programs for concurrent controlled medications.[45]

Toxicity

Signs and Symptoms of Overdose

Morphine can potentially be a lethal medication when not used properly.[46] This medication causes a host of symptoms related to CNS depression. Severe respiratory depression is the most feared complication of morphine in cases of overdose. Acute morphine overdose can present with a variety of symptoms, including respiratory depression, skeletal muscle flaccidity, cold and clammy skin, hypoglycemia, bradycardia, hypotension, constricted pupils, pulmonary edema, somnolence progressing to coma, partial or complete airway obstruction.

Management of Overdose

The initial management is to secure the airway, breathing, and circulation. Intubation and mechanical ventilation may be required in severe overdose. Advanced cardiac life support should be provided for cardiac arrest or life-threatening arrhythmias. Immediate injection of naloxone is needed to reverse the effects of morphine. Intranasal naloxone is also available. Bystander administration of the naloxone nasal spray provides rapid absorption and could be a potentially life-saving intervention for opioid overdose.[47] In individuals who are physically dependent on opioids, naloxone administration can precipitate acute withdrawal symptoms. Since naloxone’s duration of action is shorter than that of epidural or intrathecal morphine, repeated doses may be required. Accidental overdose of intrathecal morphine due to errors, such as syringe mix-ups or incorrect vial use, has been reported. Management involves administering naloxone to reverse opioid effects, with additional measures like CSF drainage, mechanical ventilation, and blood pressure management.[48]

Enhancing Healthcare Team Outcomes

Ordering and administering morphine requires an interprofessional team of healthcare professionals, including physicians, advanced practice providers, nurses, and pharmacists.[49] However, patients may be transferred throughout the hospital while under the effects of these medications. Morphine use, monitoring, and administration can utilize many resources, including laboratory technologists, pharmacists, and nurses/nursing assistants. Without proper training and careful monitoring, often starting in the emergency department, patients can develop serious side effects and have adverse reactions to morphine. Healthcare professionals should check prescription drug monitoring programs for concurrent controlled medications.[45] A study examined the effectiveness of non-opioid analgesic interventions by evaluating their morphine-sparing effects after hip or knee arthroplasty. The analysis suggests that a reduction of 5 mg in 24-hour IV morphine consumption is a clinically meaningful threshold for reducing opioid use. This finding helps guide decision-making in pain management, especially in older patients undergoing orthopedic surgery.[50] The clinician is responsible for coordinating the care, which includes the following:

• Ordering the drug
• Monitoring the patient for signs and symptoms of respiratory depression [51]
• Administering the drug
• Consulting pharmacist about the use of morphine with other medications that can cause respiratory depression
• Consulting specialist if an overdose or allergic reaction occurs
• Physicians and pharmacists should check prescription drug monitoring programs for concurrent controlled medications [45]
• Consulting with the radiology if a patient has received morphine before imaging
• Consulting with the cardiologist if using morphine in a STEMI [52]
• Immediate care by the emergency medicine team and consulting critical care physician and toxicologist in case of overdose

An interprofessional team approach and clear communication among clinicians, pharmacists, and nurses are crucial to decreasing potential adverse effects and improving patient outcomes related to morphine therapy.