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Morphine Overdose

Morphine is an opioid analgesic, and its use may either accidentally or intentionally lead to life-threatening overdose. Respiratory depression is the most important manifestation, while pinpoint pupils, drowsiness, and stupor are often encountered. The diagnosis can be made by clinical findings and urine testing. Treatment includes administration of naloxone intravenously and depending on the severity of overdose, assisted ventilation and other supportive measures may be required.


Presentation

Marked respiratory depression, pinpoint pupils, drowsiness, and stupor are main clinical findings in patients with morphine overdose [10]. Respiratory depression may be severe enough to cause apnea and cessation of breathing. Additional symptoms include nausea, vomiting, marked constipation, and pruritus, while hypotension and renal failure may also be seen. Compartment syndrome and rhabdomyolysis are also documented in some cases. All of these adverse effects eventually lead to marked hypoxia, which can cause life-threatening complications. For this reason, a very high clinical suspicion is needed, so that early recognition of opioid overdose can be made.

Pathologist
  • He felt that the job of hospital pathologist was generally to confirm diagnosis on death certificate. This he did in all honesty. On Feb. 23/83 charts of all prenatal deaths were being checked by Dr.[theinterim.com]
  • The toxicology report indicated the level of Gabapentin in Peterson's blood was six times higher than therapeutic levels, but both the coroner and forensic pathologist agreed she died from respiratory failure caused by an overdose of morphine.[usatoday.com]
  • A forensic pathologist told the inquest that Mr Whiley had heart disease, had suffered a stroke a week earlier and another stroke on the night he died.[abc.net.au]
  • An autopsy found a level of morphine in the baby’s body that a pathologist testified could have been lethal for an adult.[globalnews.ca]
  • It didn't take long for the pathologist at the Harris County medical examiner's office to determine what killed Jadalyn Diana Elizabeth Williams.[houstonchronicle.com]
Fatigue
  • […] lips, skin, and fingernails Dizziness and drowsiness Weak and thready pulse Muscle flaccidity Shallow and difficult breathing Memory loss Headaches Dry mouth Seizures and tremors Loss of appetite Difficulty urinating Gastrointestinal spasms Extreme fatigue[harborvillageflorida.com]
  • Heart attack may present as fatigue / dizziness/ chest pain or backache/ difficulty in breathing. ECG confirms the diagnosis. Wish you well.[justanswer.com]
  • […] respiratory depression, extreme somnolence, stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constipation, fatigue, dizziness, nausea, lightheadedness, headache, dry mouth, pruritus, diaphoresis, bradycardia and hypotension.[healthquestions.medhelp.org]
  • Symptoms of adrenal insufficiency may include e.g. nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or low blood pressure.[medicines.org.uk]
Anemia
  • Six year old Gina Lynn Williams was prescribed fifteen milligrams of the painkiller combats symptoms of her sickle cell Anemia but. But given ten times that amount and days later she was dead.[abcnews.go.com]
  • She'd spent a week there being treated for severe pain in her legs caused by sickle cell anemia, a disease she had lived with since birth.[houstonchronicle.com]
Intravenous Administration
  • Treatment mandates intravenous administration of an opioid antagonist, naloxone, whereas supportive measures such as assisted ventilation and fluid administration, depend on the general condition of the patient.[symptoma.com]
Nausea
  • This drug’s side effects may involve: diarrhea insomnia headache dry mouth weight loss drowsiness constipation appetite loss stomach pain taste changes sweating, chills flushing, pruritus thrombocytopenia nausea & vomiting decreased sex drive uncontrollable[healthblurbs.com]
  • Other symptoms of morphine overdose include severe constriction of pupils (pinpoint pupils), marked constipation, drowsiness, nausea, and vomiting.[symptoma.com]
  • Common signs and symptoms which may indicate the occurrence of a morphine overdose includes: Cold and clammy skin Pinpoint pupils Nausea and vomiting Severe constipation Lowered blood pressure Irregular heartbeat and palpitations Bluish discoloration[harborvillageflorida.com]
  • Nausea. Vomiting. Severe constipation. Severely slowed or irregular breathing. Slow heartbeat. Limp muscles. Severe sleepiness. Loss of consciousness. Coma.[drugabuse.com]
  • […] symptoms may be present: Bluish-colored fingernails and lips Coma Constipation Difficulty breathing, shallow breathing, slow and labored breathing, no breathing Drowsiness Pinpoint pupils Possible seizures Muscle damage from being immobile while in a coma Nausea[morphineaddictionhelp.com]
Red Eye
  • eyes, double vision, miosis menstrual irregularity, amenorrhea Morphine can cause far more serious side effects or drug allergy symptoms that require immediate health care attention, such as: rash hives seizures cyanosis confusion skin itching blurred[healthblurbs.com]
Leg Pain
  • The case is reported of a 45-year-old woman who was being treated for chronic back and right leg pain with intrathecal morphine administered via a subcutaneous continuous-infusion device.[ncbi.nlm.nih.gov]
  • The patient, who suffered depression and back and leg pain, allegedly told Dr Molnar she knew a nurse who could help her inject it at home. But the nurse did not exist and Dr Molnar did not attempt to verify the patient's claim, the board heard.[smh.com.au]
  • I wanted to ask anyone if you have ever heard of leg pain associated with tablets of morphine, I woke up at night and my legs felt like they were on fire. I am about to go off 300mg er morphine and 60mg norco daily, cold Turkey![healthquestions.medhelp.org]
Stupor
  • Other symptoms of overdose are pinpoint pupils, drowsiness, stupor and severe constipation.[symptoma.com]
  • Here is a list of the most common signs of overdose with morphine: clammy skin cold skin coma convulsions pinpoint pupils extreme somnolence (sleepiness) reduced blood pressure severe respiratory depression slow and shallow breathing stupor vomiting Morphine[drug.addictionblog.org]
  • Decreased level of consciousness CNS depression may bring about drowsiness, lethargy, stupor and eventually coma when managements are not instituted [1, 2, 3, 4]. Muscle weakness The skeletal muscles are also affected leading to flaccidity.[overdoseinfo.com]
  • […] respiratory depression, extreme somnolence, stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constipation, fatigue, dizziness, nausea, lightheadedness, headache, dry mouth, pruritus, diaphoresis, bradycardia and hypotension.[healthquestions.medhelp.org]
Stupor
  • Other symptoms of overdose are pinpoint pupils, drowsiness, stupor and severe constipation.[symptoma.com]
  • Here is a list of the most common signs of overdose with morphine: clammy skin cold skin coma convulsions pinpoint pupils extreme somnolence (sleepiness) reduced blood pressure severe respiratory depression slow and shallow breathing stupor vomiting Morphine[drug.addictionblog.org]
  • Decreased level of consciousness CNS depression may bring about drowsiness, lethargy, stupor and eventually coma when managements are not instituted [1, 2, 3, 4]. Muscle weakness The skeletal muscles are also affected leading to flaccidity.[overdoseinfo.com]
  • […] respiratory depression, extreme somnolence, stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constipation, fatigue, dizziness, nausea, lightheadedness, headache, dry mouth, pruritus, diaphoresis, bradycardia and hypotension.[healthquestions.medhelp.org]
Neglect
  • The state health department has found that neglect occurred at a Bloomington assisted living facility when a client was given an overdose of narcotics by staff.[twincities.com]
  • Trombone was sentenced to 50 years in prison on the child endangerment charge, 10 years on a charge of neglect of a dependent person and five years for being a felon in possession of a firearm.[desmoinesregister.com]
Encephalopathy
  • Thus, delayed hypoxic leukoencephalopathy is a rare complication of hypoxic-ischemic encephalopathy, occurring in 2.75% of victims of carbon monoxide poisoning. It typically manifests two to 40 days after apparent recovery from an obtunded state.[ncbi.nlm.nih.gov]
Lethargy
  • Decreased level of consciousness CNS depression may bring about drowsiness, lethargy, stupor and eventually coma when managements are not instituted [1, 2, 3, 4]. Muscle weakness The skeletal muscles are also affected leading to flaccidity.[overdoseinfo.com]

Workup

To make the diagnosis, clinical criteria may be often sufficient, but findings on clinical examination may be supported by data from patient history. Information regarding prior use of opioids or other substances, together with the duration and onset of symptoms may be valuable in determining the cause. A particular issue that is often not addressed is concomitant use of other substances such as acetaminophen, which is often prescribed together with opioids as a single formulation [2]. To make a definite diagnosis, urine or blood tests that can qualitatively determine the presence of morphine and other opioids may be performed [11]. Usually, urine tests may be positive if opioids were used between 1-4 days prior, while oral fluid may yield positive results if samples are drawn between 5-48 hours after ingestion [11].

Hepatic Necrosis
  • Too much acetaminophen can injure the liver via a process known as hepatic necrosis. Should this sort of liver damage progress, it can ultimately lead to complete liver failure.[americanaddictioncenters.org]

Treatment

Administration of naloxone, an opioid antagonist agent, is imperative in managing morphine overdose patients [2] [10]. This drug is able to reverse all of the effects caused by excessive doses of morphine and its action is evident in less than two minutes if administered intravenously. It is also possible to give this drug via intramuscular route, while the oral intake is avoided because of significantly reduced potency. Because of a much shorter half-life compared to opioids, naloxone administration is usually repeated and depends on the severity of the overdose.

In addition to naloxone, various supportive measures may be necessary. The use of assisted ventilation in severe respiratory depression, as well as administration of fluids in hypotension and rhabdomyolysis, may be of significant benefit.

Prognosis

The prognosis of morphine overdose depends on several factors, including the dose, severity of respiratory depression and other symptoms, as well as time of treatment initiation. It is important to emphasize that fatal outcomes may be seen in opioid overdose, but with timely treatment, patients may recover fully.

Etiology

Morphine overdose can stem from various situations [2]:

  • Accidental intake of higher amounts of the drug.
  • Intentional intake due to opioid abuse.
  • Inadequate prescription by the physician that did not set the right dose or the right amount of the drug depending on the route of administration.
  • Use of opioids in patients who are known to be at an increased risk for drug abuse (prior alcohol or substance abusers).
  • Improper therapy conduction.

Epidemiology

It is estimated that more than 3% of adults in the United States receive long-term opioid therapy for non-cancer related pain [4]. Male gender has shown to be significant risk factor for overdose, as much higher death rates are observed across all age groups in males, while studies regarding ethnicity predilection have shown increased mortality in Caucasians [5]. Although opioid abuse is seen in individuals of all age, adults between 45-54 years of age have shown highest mortality rates [5]. Studies conducted in the United States show that there is a marked rise in deaths from opioid overdose, with over 15,000 occurring in 2010 [6]. Opioid analgesics have shown to be the most common drugs that caused unintentional deaths from overdose in the past decade, indicating that abuse is not the sole reason for fatal outcomes [5]. Moreover, an approximate 100% increase in opioid prescription has been observed and it has become evident that various flaws in prescription, use, administration and wide availability promote such rates [5] [7].

Sex distribution
Age distribution

Pathophysiology

There are three main types of opioid receptors: mu (µ), kappa (κ), and delta (δ) and various subsets have been identified in the human body [8]. Morphine activates the μ-opioid receptors and exerts various effects in the body [1] [9]:

  • Inhibition of nociceptive signals - The primary role of opioid drugs is modulation of pain signals, which is thought to be achieved by inhibition of nociceptive stimuli at several levels of the nervous system. Namely, pain signals are inhibited in the primary afferent fibers and are further diminished by inhibition of calcium-mediated ion channel opening in the presynaptic cleft and potassium channels in secondary afferent neurons. Additionally, morphine supposedly reduces pain by promoting GABA-mediated signaling in the brainstem, leading to further inhibition of pain signaling pathways. The thalamus and some other higher structures are also presumed to be the sites of action.
  • Respiratory depression and other CNS effects - One of the most deleterious effects of opioids, including morphine, is reduced breathing via inhibition of brainstem mechanisms that involve partial pressures of CO2. It is established that respiratory depression may only occur when higher doses are administered, but patients with accompanying lung diseases may develop this adverse effect even at lower doses of morphine. Sedation, euphoria, nausea, and vomiting as a result of brainstem-mediated activation, as well as the rigidity of larger muscles in the trunk are also effects of morphine in the CNS. Pupil constriction, as a result of interaction between opioids and the parasympathetic system, is almost always seen in opioid overdose and is dose-independent.
  • Constipation - Opioid receptors are abundant in the GI tract and their stimulation leads to constipation. Reduced gastric acid production and diminished motility of both small and large intestines are observed and are thought to be the main contributing factors.

Other effects of morphine include the development of pruritus (as a result of histamine release), depression of renal function, whereas modulation of the immune response has also been documented [9].

When the use of opioids is carefully designed and carried out, little or no adverse effects may develop, as the hepatorenal system is efficient in excreting morphine through urine. When an excessive amount of morphine are introduced into the body, however, excretion pathways become saturated and reach a maximal capacity of clearing the drug out of the system, which leads to significantly higher concentrations in blood and much greater potency to cause adverse effects. Moreover, it is known that morphine metabolites,morphine-3-glucuronide and morphine-6-glucuronide are powerful neuroexcitatory and analgesic compounds, respectively, and in the setting of increased intake or reduced clearance in patients with renal disease, they may cause adverse effects [1].

Prevention

Opioid overdose is recognized as a major problem in the United States, and various legislative steps have been taken to reduce the burden of such events. Implementation of prescription-monitoring programs, restricted use of opioids in various patient populations that are shown to be at an increased risk for overdose and suppression of drug abuse among adolescents are some of the strategies [7] [12].

Summary

Morphine, derived from Papaver somniferum and its seed, opium, is one of the most powerful agents used in the management of pain. However, because of its potency, propensity for abuse and development of tolerance, morphine overdose may occur and result in potentially fatal consequences. This opioid is a full agonist at the µ-opioid G-protein-coupled receptors that are distributed in various tissues, but most prominent effects are achieved in the central nervous system, where inhibition of pain signals occurs on various levels [1]. Under physiological conditions, nociceptive stimuli travel through the primary afferent neurons and reach the dorsal horn of the spinal cord, where they are transmitted into secondary afferent neurons and into the CNS. Presumably, µ-opiod receptors are situated both in primary and secondary afferent neurons in the spinal cord, and prevent pain stimuli from reaching the CNS by either direct inhibition, or by attenuating normal conduction signaling via suppression of Ca and K channel opening [1]. Additionally, these receptors are hypothesized to modulate pain signaling in higher structures, such as the thalamus and the brain stem, which may explain why opioids are superior drugs to other analgesics (for ex. non-steroidal anti-inflammatory drugs). In addition to pain modulation, opioids exert effects on several other organs, principally the lungs, the gastrointestinal tract, cardiovascular system, and other. The development of tolerance, however, is a major disadvantage with opioid use and because increases in dosages are frequently required, individuals are prone to overdose and development of symptoms that may be life-threatening. Respiratory depression is the most important adverse effect that may develop, which may be severe enough to cause apnea and respiratory failure. Other symptoms of overdose are pinpoint pupils, drowsiness, stupor and severe constipation [2]. To make the diagnosis, detailed patient history, a thorough physical examination that will identify clinical criteria and urine testing for opioids should be included. Treatment mandates intravenous administration of an opioid antagonist, naloxone, whereas supportive measures such as assisted ventilation and fluid administration, depend on the general condition of the patient. Because increased rates of opioid overdose have been observed in recent time, various strategies have been implemented in terms of more strict indications for use of this class of drugs in pain management [3], as well as prescription-monitoring programs. Additionally, opioids are contraindicated in various patient populations, including those suffering from a chronic obstructive pulmonary disease (COPD) and other chronic lung diseases, patients in whom hepatorenal functions are impaired, in the case of head injury and it is contraindicated in pregnancy. Most importantly, patients with prior substance abuse and family history of a psychiatric disease should not use opioid analgesics because of a significantly higher risk for abuse. Morphine is a powerful antinociceptive agent, but it must be used cautiously and under specific circumstances, since overdose may lead to fatal outcomes.

Patient Information

Morphine belongs to the group of opioid drugs, one of the most potent painkillers used in medical practice. It is frequently used for management of both acute and chronic severe pain. An overdose of morphine may occur as a result of accidental ingestion or injection of a higher dose, or because of intentional abuse, but it may also occur due to inappropriate prescription. In fact, the use of opioids in the United States has risen dramatically in the past years, together with an increase in cases of overdose and fatal outcomes, reaching up to 15,000 deaths in 2010. Mortality rates have shown to be much higher among males, while both genders exhibited highest mortality rates between 45-54 years of age according to studies conducted in the US. Morphine exerts its effects on mu (µ)-opioid receptors and very effectively reduces pain by interrupting signaling pathways in the spinal cord and the brain. However, because tolerance may quickly develop and lead to the need for increasing doses to cope with pain; effects in other organs, including the lungs, gastrointestinal tract, the eyes and the kidneys are seen. Respiratory depression is the most feared and most important adverse effect seen in morphine overdose, which is characterized by marked reduction in breathing rate that may be severe enough to cause cessation of breathing (apnea). Apnea may be life-threatening for the patient as severe oxygen deficiency develops throughout the body within minutes. Other symptoms of morphine overdose include severe constriction of pupils (pinpoint pupils), marked constipation, drowsiness, nausea, and vomiting. The diagnosis is often made based on clinical findings and confirmation can be obtained by qualitative testing in various patient samples, most commonly urine. Opioids can be detected in urine if consumed up to 4 days prior to testing, while samples from oral cavity may recover morphine if taken up to 48 hours prior. The mainstay of treating morphine overdose patients is the administration of naloxone, a drug that reverses the effects of morphine by binding to the same receptors. Its effects are seen within minutes after administration, but repeated use is often necessary because of much shorter duration of effects than morphine. Respiratory support with assisted ventilation and oxygen therapy are frequently necessary, while other supportive measures such as blood pressure control and adequate management of other symptoms are beneficial. Despite available treatment, morphine overdose may be fatal, often due to reasons that can be influenced upon significantly. Firstly, opioids should never be given to patients in whom an increased risk for overdose exists, such as those with various lung diseases and who had a history of substance abuse. Secondly, carefully designed use of morphine is necessary to prevent the risk of overdose. Finally, surveillance programs that monitor and control the use of opioids in everyday life, as well as attempts to reduce abuse of this drug among adolescents, are key steps in preventing morphine overdose.

References

Article

  1. Katzung BG,Masters SB, Trevor AJ. Basic & Clinical Pharmacology. 13th edition. New York: McGraw-Hill Medical; 2014.
  2. Boyer EW. Management of Opioid Analgesic Overdose. N Engl J Med. 2012;367(2):146-155.
  3. Gwira Baumblatt JA, Wiedeman C, Dunn JR, Schaffner W, Paulozzi LJ, Jones TF. High-risk use by patients prescribed opioids for pain and its role in overdose deaths. JAMA Intern Med. 2014;174(5):796-801.
  4. Dunn KM, Saunders KW, Rutter CM, et al. Opioid prescriptions for chronic pain and overdose: a cohort study. Ann Intern Med 2010;152:85-92.
  5. Okie S. A flood of opioids, a rising tide of deaths. N Engl J Med. 2010;363:1981–1985.
  6. Dart RC, Surratt HL, Cicero TJ, et al. Trends in opioid analgesic abuse and mortality in the United States. N Engl J Med. 2015;372(3):241-248.
  7. Compton WM, Volkow ND. Major increases in opioid analgesic abuse in the United States: concerns and strategies. Drug Alcohol Depend. 2006;81(2):103-107.
  8. Yekkirala AS, Kalyuzhny AE, Portoghese PS. Standard opioid agonists activate heteromeric opioid receptors: evidence for morphine and [d-Ala(2)-MePhe(4)-Glyol(5)]enkephalin as selective μ-δ agonists. ACS Chem Neurosci. 2010;1(2):146-154.
  9. Messmer D, Hatsukari I, Hitosugi N, Schmidt-Wolf IG, Singhal PC. Morphine reciprocally regulates IL-10 and IL-12 production by monocyte-derived human dendritic cells and enhances T cell activation. Mol Med. 2006;12(11-12):284-290.
  10. Porter RS, Kaplan JL. Merck Manual of Diagnosis and Therapy. 19th Edition. Merck Sharp & Dohme Corp. Whitehouse Station, N.J; 2011.
  11. Verstraete AG. Detection times of drugs of abuse in blood, urine, and oral fluid. Ther Drug Monit. 2004;26(2):200-205.
  12. Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain—United States, 2016. JAMA. 2016;315(15):1624-1645.

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Last updated: 2019-06-28 11:44