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.

• 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]

• Chills

  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]

  Skin may appear cool and clammy and a severe chill called hypothermia may develop. Shrunken pupils - Morphine may cause the pupils to constrict and appear pin-pointed in size. [news-medical.net]

  Less common Blurred vision bulging soft spot on the head of an infant burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings change in the ability to see colors, especially blue or yellow chest pain or discomfort chills [mayoclinic.org]

• Shivering

  […] urination pale or blue lips, fingernails, or skin pale skin pinpoint red spots on the skin poor coordination pounding in the ears puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue restlessness shakiness and unsteady walk shivering [mayoclinic.org]

  Seek medical attention right away if you have symptoms of serotonin syndrome, such as: agitation, hallucinations, fever, sweating, shivering, fast heart rate, muscle stiffness, twitching, loss of coordination, nausea, vomiting, or diarrhea. [drugs.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]

• Rigor

  I will tell you that...the things you have to go through to be an Expert are quite rigorous. [justanswer.com]

• Yawning

  By Richard Klasco, M.D Photo Credit Ask Well Photo Credit Why Do We Yawn? Reading about yawning makes people yawn. You are probably yawning right now. By Roni Caryn Rabin Latest Search Latest Articles Search Articles 13843 results for sorted by [nytimes.com]

  Typically, opioid withdrawal symptoms include : Muscle aches, pains, and cramps Restlessness Anxiety Insomnia Watery eyes and runny nose Stomach pain Yawning frequently Goosebumps Diarrhea Loss of appetite Nausea or vomiting Blurry vision or dilating [recoveryfirst.org]

  Withdrawal symptoms may include some or all of the following: restlessness, tearing, runny nose, yawning, perspiration, gooseflesh, or restless sleep during the first 24 hours. [everydayhealth.com]

• Rhinitis

  Withdrawal from morphine can cause: tearing rhinitis diarrhea insomnia mydriasis uneasiness nausea, vomiting back & leg aches bouts of sneezing cold & hot flashes abdominal cramps excessive sweating chills, goose bumps muscle spasms, twitching increased [healthblurbs.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]

  In addition, morphine stimulates the vomiting centre of the brain causing nausea and vomiting. Morphine and codeine cause more nausea than other opioids. There may be drying of the mouth as well. [news-medical.net]

  Common side effects of Avinza include constipation, nausea, drowsiness, headache, and itching. [everydayhealth.com]

  Other symptoms of morphine overdose include severe constriction of pupils (pinpoint pupils), marked constipation, drowsiness, nausea, and vomiting. [symptoma.com]

  The physician may also prescribe medications to relieve symptoms like nausea or anxiety while the individual detoxes from morphine. [recoveryfirst.org]

• Abdominal Pain

  Tell your doctor right away if you have any serious side effects, including: mental/mood changes (such as agitation, hallucinations, confusion), difficulty urinating, vision changes, slow/fast heartbeat, severe stomach / abdominal pain, signs of your [webmd.com]

  Biliary colic and subsequent severe abdominal pain is common in morphine overdose. With high doses, muscle rigidity and abnormal movement of the limbs and muscles called myoclonus may manifest. [news-medical.net]

• Anxiety Disorder

  A bag of prescription pills used to treat anxiety disorders was also found, along with three flat-screen televisions, counterfeit bills and a gun holster with rounds of ammunition. [desmoinesregister.com]

• 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]

• Irritability

  Agitation or irritability. Changes in heartbeat (either rapid, irregular, or slowed). Confusion. Difficulty urinating or pain during urination. Drowsiness. Dry mouth. Extreme sleepiness. Fainting. Fever. Hallucinations (either visual or auditory). [drugabuse.com]

  Over the next 72 hours, these symptoms may increase and other symptoms of increasing irritability, anxiety, weakness, twitching and muscle spasms, abdominal and muscle cramps, hot and cold flashes, insomnia, and increases in body temperature, blood pressure [everydayhealth.com]

• Clumsiness

  […] blindness overbright appearance of lights problems with muscle control stomach discomfort or upset trouble sleeping uncontrolled eye movements Incidence not known Abnormal dreams change in walking and balance change or problem with discharge of semen clumsiness [mayoclinic.org]

  Do not drive a car or ride a bike if morphine makes you sleepy during the daytime, gives you blurred vision or makes you feel dizzy, clumsy or unable to concentrate or make decisions. [beta.nhs.uk]

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].

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.

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.

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.

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].

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].

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].

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.

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.

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