Morphine Drug Profile in Applied Pharmacology

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The chemical name, generic name, and Australian trade names for the drug

The chemical name of morphine is 5 alpha 6 alpha 7,8-Didehydro-4,5-epoxy-17-Methyl-morphinan-3,6-diol. Morphine trade names include Kapanol, AVINza, MS Contin (morphine sulphate controlled-release), MST continus, MSIR, Oramorph SR, Roxanol. Morphine is a pure opioid agonist, and its therapeutic action is analgesic medication. It is the prototypical opioid (Newby, Wilkie & Stevens 2009, p.399). This appears in “management of pain not responsive to narcotic analgesics, dyspnea associated with acute left ventricular failure and pulmonary oedema, managing pain before and after surgery, used to facilitate the induction of anaesthesia, used as analgesia during labour” (Bengtsson et al. 2009, p.1087).

The approved indications for the drug

Morphine and other drugs interact primarily by increasing the side effects of either drug. Morphine is incompatible with MAO inhibitors like isocarboxazid phenelzine. It has severe side effects. That is why the patient should wait for not less than 14 days for the MAO inhibitors to clear from the body (Becker et al., 2010, p.85). Interaction of MAO inhibitors and opioid analgesics is proven to produce severe side effects, such as an extreme increase in body temperature and seizures. Metoclopramide (anti-emetic) increases gastrointestinal motility, therefore, speeding up the onset and sedative effects of orally administered morphine. It also treats severe, acute, or chronic pain and is effective for managing post-injury stress response, which heightens the presence of anxiety and recurring pain. If the stress is not managed, then it becomes a risk factor that is capable of causing organ failure and even trauma death if the condition is serious enough. It is also very effective when trying to treat shortness of breath or breathlessness. Moreover, surgeons favour it as anaesthesia during surgery due to its numbing effect.

The approval of the drug for paramedic use in South Australia

Antibiotics such as rifampicin decrease the effects of opioids, and erythromycin increases. Anti-epilepsy drugs such as barbiturates can speed up opioid metabolism in the liver. There is a significant increase in plasma availability of morphine in patients treated with tricyclic antidepressants like clomipramine and amitriptyline. Rapid opiate detoxification regime is an example of drug interaction, a small dose of naloxone (0.5mg) is injected into opioid-dependent people, and withdrawal syndrome is seen very similar to those observed following abrupt withdrawal of opioids except the syndrome that initiates in minutes and subsides in two hours.

Morphine is available in different formulations and strengths. Injectables 0.5-25 mg/mL strength and oral solutions 2-20 mg/mL immediate and control release tablets and capsules 15-200 mg and suppositories 5-30 mg. Following administering of morphine in any form, strict medical follow up is important and special tests may be required in the monitoring of patient’s progress with the drug, which has severe side effects, including addiction to the drug (Olesen 2010, p.190). The pKa of morphine (8.0) is greater than physiologic pH, thus after IV injection, only about 10-20% is un-ionised. This property, combined with its low lipid solubility, limits its ability to penetrate tissues hence the slower penetration of morphine in and out of the brain. Therefore, analgesia and respiratory effects do not reflect in the plasma levels. It is important to indicate here that morphine is one of the best pre-hospital pain relievers, but one should carefully consider the dosage they administers to the patient as an overdose may prove even riskier than the condition that one tries to offset.

Medicines known to undergo clinically relevant interactions with the drug in humans

Metabolism of morphine takes place principally by conjugation at position 3 and position 6. At position 3, it gives morphine-3-glucuronide (M3G), and at position 6, Morphine-6-Glucuronide (M6G) is acquired (Bryant, & Knights 2011, p.23). M- Receptors occur in the CNS. They come in handy in pain modulation, analgesia, euphoria, respiratory depression, meiosis reduced gastrointestinal activity (Caraceni, Pigni, Brunelli 2011, p. 409). M6G contributes substantially to morphine’s analgesic effects, and M6G appears to have a more favourable side effect than morphine. There are several Over-the-Counter (OTCs) and Complementary and Alternative Medicines (CAMs) that sometimes both work faster or slower than morphine. Therefore, morphine is very important. These drugs are applicable as alternatives and can be used to either replace or complement morphine. They include Codeine, which starts to work within four hours of taking it by mouth and up to 72 hours if it is administered by patch. It works best when the remedy is administered together with aspirin or acetaminophen. Another is Hydromorphone, which effectively stems from chronic pain and starts operating within 2-4 hours of intravenous injection or 4 hours when taken through a rectal suppository. Levorphanol is very potent in its oral form, and it takes more than four hours to take effect when it is taken by mouth. It helps for acute pain relief, and the intramuscular form begins to take effect within 2 hours of injections.

Morphine has a high hepatic extraction ratio, the bioavailability of orally administered morphine is lower than IM or subcutaneous injection, but M6G is a more active compound when it is administered orally. Once absorbed, morphine distributes itself to the skeletal muscle, kidneys, liver, spleen, lungs, and some amount of it pass through the blood-brain barrier with high concentration found in the CSF. “Morphine also crosses the placental membrane…” (Pei-Jung et al. 2010, p. 241). Morphine has a hepatic extraction ratio that is equal to or greater than hepatic blood flow, indicating a high clearance of about 15-30 mL/kg per min-1. The kidneys appear to play a key role in the extrahepatic metabolism of morphine and account for about 40% of its clearance. M6G can accumulate following a chronic administration in a renal impaired patient. “Elimination of morphine occurs primarily as renal excretion of M-3-G, and its terminal elimination half-life after intravenous administration is normally 2 to 4 hours” (Yao-Chang et al. 2010, 2010, p.8). About 90% of a single morphine dose goes out through the urine within the first 72 hours, with 75% being present as M3G and less than 10% unchanged morphine. The medicine has a short half-life of 1.5- 7 hours, and M6G has a half-life of about 4+/- 1.5 hours. Taken by mouth, morphine being a versatile drug, has a plasma half-life of 2-2.5 hours (Dehghan et al. 2010, p.709). The half-life of morphine experiences the effect of reduced metabolic rate and hepatic condition of an individual.

The strength of the evidence for the interactions identified

The World Health Organization Geneva 1996 recommended morphine as a “first-line strong opioid” whose pain-relieving properties made it ideal for use in treating cancer patients. The dosage of morphine is mostly patient dependent. All the opioid doses are individual-based because the effective analgesic dose of one patient may be too high for patients to tolerate. Clearance is decreased; hence “metabolites M3G and M6G may accumulate too much higher plasma levels. Therefore drug dosage is regulated, and the patient is monitored closely to avoid the accumulation of M6G, which may lead to severe undesired side effects” (Duggan & Scott 2010, p 534). The adult oral dose is usually 60-120mg in divided doses and up to 400mg daily for opioid-tolerant patients. The oral solution is 10-20mg every 4 hours as needed.

The dosage forms and strengths available in Australia

People can abuse morphine legally or illegally when prescribing or dispensing it. A physician or pharmacist must be concerned about an increased risk of misuse or abuse of the drug due to its high rate to induce dependence when used inappropriately (Lindegaard 2010, p.188). Morphine has psychological effects, such as depressed heart rate, reduced reflexes, CNS depression, and respiratory depression, where morphine affects the brain stem respiratory centre, nausea and vomiting, flushing of face and neck due to dilation of blood vessels, reduced gastrointestinal motility leading to constipation, cramping, sweating, fixed pupils and constricted, analgesia and depressed consciousness (Vindenes et al. 2009, p. 359). It brings about euphoria, feeling of well-being, mental clouding, delirium, relaxation, drowsiness, sedation, lethargy, self-absorption, delirium.

Administration issues followed for safe, efficacious use

The drug code Standard for the Uniform Scheduling of Drugs and Poisons in Section 8 provides for the legal use of morphine, which is a controlled drug. ‘Controlled’ means here that possession without proper authorisation is illegal. This section provides that the health department must approve the drug and that one can only acquire it using a handwritten prescription. Nothing printed is permissible. The Australian government ratified the United Nations’ Anti-narcotic Act. Therefore, poppies, which are the form in which morphine grows, can only grow in Tasmania. Federal rules are very strict about this.

How the drug is bound to plasma proteins

Morphine is bound to plasma proteins at 35 %.

The unbound fraction is the remaining percentage that is 100% minus 35% which is 65% or 0.65 or 65/100 which simplifies to 13 / 20.

The volume of distribution (VD) in either litre per kilogram (L/kg) or litres (L)

The volume of the distribution of morphine to blood is 1.0 to 4.7 L/Kg. When morphine is in the system, it spreads to the brain, intestinal tract, liver, lungs and spleen. It also spreads to placental milk, and this distribution shows that morphine’s distribution surpasses the blood volume, which is why it can move from the plasma and into the rest of the body.

The volume of distribution is an important figure that allows one to determine whether the drug has reached most of the body’s internal organs. To accomplish this, one can calculate distribution at two levels. Initially, before administering the drug, the blood concentration indicates the original value, and then after taking the drug, the final concentration indicates how the body has absorbed the drug.

The usual loading dose

Not all the forms of morphine are loading doses, but its titrates can substitute its pain-relieving property. As Lagas et al. (2010, p. 1402) point out, “morphine also causes miosis, even in total darkness while marked mydriasis rather than miosis worsens hypoxia”. “Morphine produces peripheral vasodilation, which may result in orthostatic hypotension also there, can be the release of histamine and contribute to opioid-induced hypotension and cause pruritus and red eyes” (Lagas et al. 2010, p. 1401). Other adverse reactions include bradycardia, tachycardia, palpitations, coordination, urticaria, blurred vision, urinary retention, apnea, laryngospasm.

Systemic (total) clearance

It is 24ml/min/Kg, which converts to 1.44litres per hour per Kg, and so for a person weighing 70Kgs, it will be 100.8L/Hr. Metabolism of morphine takes place principally by conjugation at position 3 and position 6. At position 3, it gives morphine-3-glucuronide (M3G), and at position 6, Morphine-6-Glucuronide (M6G) (Bryant, & Knights 2011, p.23). M- Receptors occur in the CNS. They come in handy in pain modulation, analgesia, euphoria, respiratory depression, meiosis, reduced gastrointestinal activity (Caraceni, Pigni, Brunelli 2011, p. 409). M6G contributes substantially to morphine’s analgesic effects, and M6G appears to have a more favourable side effect than morphine.

It has a high hepatic clearance.
It has high first-pass extraction.

This is an important factor that requires special consideration in the administration of the drug.

The half-life of the drug

2-3 hours or 120-360 minutes.

The steady-state after commencing oral administration

3.5 half-lives. In this case, that becomes 7-10.5 hours.

Contraindications of morphine include use in patients with respiratory depression, acute bronchial asthma, and paralytic ileus as well. Morphine is used cautiously in patients with acute alcoholism, head injury, hypoxia, intracranial pressure, liver or kidney failure, epilepsy and mental illness (Hsu, &Parker 2004, p.56).

The dosage adjustment for age

For adults, the dosage translates to 20-30mg, and for the elderly, it is 15-20 mg. Per hour treatment dosages also vary. For adults, it is 0.5-2.0mg, while for the elderly, it should fall between o.5mg and 1.5mg.

18. Patients allergic to narcotics should not use morphine too. Overdosage symptoms include meiosis, seizures, cold or clammy skin, fluid in the lungs, slowed pulse rate, blue fingernails, flaccid muscles, low blood pressure, spasms of the stomach or intestinal tract, CNS depression, circulatory collapse, cardiopulmonary arrest, coma and death (Suski 2010, p.683). Patients on morphine should strictly avoid alcohol and substances that contain alcohol too.

The dosage adjustment for in individuals with hepatic disease

Morphine metabolises in the liver. Therefore, in the event of liver disease, the dosage will require an alteration to suit the condition suffered by the patient. Otherwise, the drug will be of no use to the patient. It is also important to consider the type of method used to administer the drug, whether oral or intravenous.

Being an endogenous opioid, morphine has similar characteristics to endorphins, which is why it relieves pain and induces sleepiness and drowsiness.

The potential for overdose associated with the drug, the clinical signs and symptoms expected and the patient treatment plan

Overdose is dangerous to liver functioning. In the worst cases, it could result in asphyxiation, which refers to the inability to ventilate. This means that neither oxygen nor carbon dioxide gets exchanged across the ventilation surfaces. If not treated immediately, this may result in death or respiratory depression and renal failure. To treat an overdose that results in any of the above consequences, doctors can administer naloxone, which reverses the effect of morphine.

References

Becker, G. et al., 2010. Precipitated and Conditioned Withdrawal in Morphine-Treated Rats. Psychopharmacology, 209(1), pp. 85-94.

Bengtsson, J., et al., 2009. The Influence of Age on the Distribution of Morphine and Morphine-3-glucuronide Across the Blood-Brain Barrier in Sheep. British Journal of Pharmacology, 157(6), pp. 1085-1096.

Bryant, B.,& Knights, K., 2011.Pharmacology for Health Professionals, 3rd Edition, Australia: Mosby, Elsevier Press.

Caraceni, A., Pigni, A., Brunelli, C., 2011. Is Oral Morphine Still the First Choice Opioid For Moderate to severe cancer pain? Palliative Medicine,25(5), pp. 402-409.

Dehghan, R., et al., 2010. The Use of Morphine to Control Pain in Advanced Cancer: An Investigation of Clinical Usage in Bagladesh. Palliative Medicine, 24(7), pp.707-714.

Duggan, S., &Scott, L., 2010.Morphine/Naltrexone.CNS Drugs, 24(6), pp. 527-538.

Hsu, T., & Parker, S., 2004. Are inhalers with spacers better than nebulizers for Children with asthma? Journal of Family Practice, 53, pp. 55-7.

Lagas, J., et al., 2010. Lethal morphine intoxication ina patient with a sickle cell crisis And renal impairment: Case report and a review of the literature. HET, 30(9), pp. 1399-1403.

Lindegaard, C., et al., 2010. Pharmacokinetics of Intra-Articular Morphine in Horses with Lipopolysaccharide-Induced Synovitis. Veterinary Anaesthesia & Analgesia, 37(2), pp. 186-195.

Newby, N., Wilkie, M., & Stevens, E., 2009. Morphine Uptake, Disposition, and Analgesic Efficacy in the Common Goldfish. Canadian Journal of Zoology,87(5), pp. 388-399.

Olesen, A. et al., 2010. Different effects of Morphine and Oxycodone in Experimentally Evoked Hyperalgesia: A Human Translational Study. British Journal of Clinical Pharmacology, 70(2), pp. 189-200.

Pei-Jung et al., 2010. Morphine Enhances Tissue Content of Collagen and Increases Wound Tensile Strength. Journal of Anaesthesia 24(2), pp. 240-246.

Suski, M., et al., 2010.Co-Administration of Dextromethorphan and Morphine: Reduction of Post-Operative Pain and Lack of Influence on Morphinem Metabolism. Clinical Pharmacology and Toxicology, 107(2), pp. 680-684.

Vindenes, V., et al., 2009.Different Effects on Dopamine Release in Nucleus Accumbens in Mice by the Morphine Metabolites. Basic & Clinical Pharmacology &Toxicology,105(5), pp.357-360.

Yao-Chang, C., et al., 2010. Enhancement of Tolerance Development to Morphine in Rats Prenatally Exposed to Morphine, Methadone, and Buprenorphine. Journal of Biomedical Science, 17(1), pp. 1-10.

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