Osteoarthritis and Hip Replacement Case

INTRODUCTION

Osteoarthritis. This is the deterioration of joint cartilages, resulting to bone rubbing off against bone. It is accompanied by pain during movement, tenderness, stiffness and a grating sensation during movement (Glyn-Jones S. et al., 2015). An X-ray or a Magnetic Resonance Imaging (MRI) is used for imaging diagnosis together with joint fluid analysis. A treatment plan of analgesics and non-steroidal anti-inflammatory drugs are accompanied by surgical procedures such as joint replacement and realigning of the bones (Goldman L. et al., 2016). Pasha Smirnov is an 83 year old man with a past medical history of severe osteoarthritis. For the past 5 years he has been experiencing persistent hip joint pain despite being fit with no other relevant medical history. He had an uneventful total hip replacement surgery and was back in the orthopedic ward for recovery. He could only manage small food amounts and fluids due to his persistent nausea, frequent vomiting and mild dyspepsia. There had been no bowel movement from surgery day and there was mild pruritus to his trunk and back. There was no infection on his hip wound. He described to the nurse during a pain assessment that he was experiencing moderate pain (5-6) when mobile and mild pain (2-3) when immobile. Furthermore, he experienced persistent nausea without vomiting and on the assessment day he was experiencing back and chest itch with no rash. For those tackling complex cases like Pasha’s in a healthcare dissertation, seeking healthcare dissertation help can provide valuable insights and support.

In this case study we aim to explain the pharmacological processes that occur when he takes his medication that may either cause some of his symptoms or aimed to reduce them. His medicine management would also be discussed in detail to evaluate his medication in relation to his recovery and the nurse’s role in his recovery together with safe practice while he is undergoing treatment in the hospital.

BODY

Mr. Smirnov had been put on a medication regime to accelerate his recovery process and mange his post-operation symptoms. He had been on intravenous (IV) morphine patient-controlled analgesia (PCA) of 50mg with a concentration of 1mg/ml without a continuous or background infusion. It was administered as 1mg bolus with a lock out period of 5 minutes and a total dose of 12mg/hr. Morphine is a moderate pain reliever that acts on the central nervous system to manage acute and chronic pain. There is 100% bioavailability of the drug in the blood because it does not experience the first pass effect and bypassed the breakdown process in the gastrointestinal tract (Bertram G. 2018). This route of administration is the most rapid and its analgesic effect was immediately felt in 5 minutes and maximum effect is in 20 minutes (Alexander S. P. H. et al., 2015).

Pharmacokinetics refers to the action of the body to the drug (Bhatt D. L. et al., 2016). After administration, the opioid was distributed in the body through physiological and chemical factors in blood. Morphine is bound to plasma proteins in the blood and during distribution it leaves the blood and localize in the highly perfused tissues such as the spleen and liver (Downing N. S. et al., 2012). It also gets into the skeletal muscles but in low concentration and accumulates with time giving a prolonged effect. Morphine is metabolized in the different areas from cellular to tissue level. It is first converted to morphine-3-glucuronide the morphine-6-glucuronide (M6G). M6G has a half-life of averagely 6.4 hours in plasma while morphine has a half-life of averagely 2.8 hours in plasma. It is converted into polar metabolites preferably glucuronides which are then excreted by the kidneys (Spahn V. et al., 2017). The metabolism can either be through hepatic P450 metabolism where there is hepatic oxidative metabolism or plasma esterase metabolism. These polar metabolites are excreted through the urine with most of it having undergone metabolism and a very small quantity still being unchanged.

Pharmacodynamics refers to the action of the drug onto the body. Morphine is a full agonist which acts through the G- protein coupled receptors found in the brain and the spinal cord at the regions that take part in the transmission and modulation of pain (Roeckel L. A. et al., 2016). Morphine has free hydroxyl groups and is conjugated to morphine-3-glucuronide (M3G) which has neuro-excitatory properties but cannot be mediated by the intended µ opioid receptors (Stein C. 2016). 10% of it is metabolized to morphine-6-glucuronide which is more active and has a higher potency than morphine (Kharasch E. D. et al., 2015). Through the G-protein coupled receptor the opioids have an effect on the neurons that transmit pain. They close the voltage gated calcium ion channels on the presynaptic neuron hence reducing the neurotransmitter generated to transmit the action potential generated and the further open the potassium ion channels on the postsynaptic neuron and cause hyperpolarization hence it is not easily excited. Through this action the pain is no longer experienced by the patient. The side effects that have been experienced by Mr. Smirnov due to morphine include euphoria which causes addiction, sedation and nausea (Volkow N. D. et al., 2016). Mr. Smirnov has been experiencing persistent nausea which has sometimes been accompanied by vomiting. It also affects the gastrointestinal tract because the stomach motility decreases as the tone increases, hydrochloric acid secretion decreases and the small intestine tone decreases with few spasms. This explains why he can only manage small amounts of food and there has been frequent vomiting. In the large intestine the peristaltic waves diminish as the tone increases delaying passage of fecal mass and water is absorbed causing constipation. This explains the lack of bowel movement for three days. Pruritus also occurs with flushing and warming of the skin together with itchiness. This explains his back and chest itching without a rash (Liu X. Y. et al., 2011). Morphine can also interact with CNS depressants, muscle relaxants, cimetidine, monoamine oxidase inhibitors, anticholinergics, P- glycoprotein inhibitors and diuretics.

Paracetamol (acetaminophen) is an analgesic and antipyretic drug that was orally administered to Mr. Smirnov. It was administered to manage his mild pain and a dose of 1 gram every 6 hours was given and a maximum of 4 grams was administered per day. Unlike morphine, acetaminophen acts on both the central nervous system and the peripheral nervous system (Elina T. et al., 2012). Acetaminophen’s bioavailability ranged between 5% - ˂100% due to the first pass effect where some of it was metabolized in the gastrointestinal tract and some of it was not absorbed into the blood stream and was excreted. The rectal route of administration would have by-passed a major part of the first pass effect with a bioavailability of 30%-≤100% (Amerongen G. et al., 2018). Its action began to be felt in 10-15 minutes with its maximum effect being after 1 hour and lasts for 6 hours. Acetaminophen was orally administered and rapidly absorbed from the gastrointestinal tract. Its absorption majorly depends on the gastric emptying with factors like food, propantheline, pethidine and diamorphine slowing down its absorption into the blood stream while factors like metoclopramide enhancing its absorption. Acetaminophen is evenly distributed in the blood with an average volume of 0.9L/kg depending on the dose and transported to different tissues in the body only 10%-20% of it is bound to the red blood cell. It is metabolized, mostly in the liver, through glucuronic acid conjugation and sulphuric acid conjugation to produce soluble metabolites such as sulphates and glucuronide. A small portion is also metabolized by cytochrome P450 into N-acetyl benzoquinone imine metabolite which is highly reactive but it is also quickly detoxified and converted into glutathione which is excreted in urine in the form of cysteine and mercapturic acid conjugates (Michael F. et al., 2011). In 24 hours, 85%-95% of the dose is excreted with 4% being unchanged paracetamol, 55% as glucuronide, 30% being sulphate, 4% as mercapturic acid and 4% being cysteine conjugates. The plasma half-life of paracetamol ranges from 1.9-2.5 hours and once a dose has been taken, its total body clearance is 4.5-5.5 ml/kg/min (Emma J. et al., 2013).

Paracetamol is a weak inhibitor of the synthesis of prostaglandins and it is a cyclooxygenase-2 inhibitor. It has analgesic and antipyretic properties which facilitates treatment of the mild pain Mr. Smirnov experienced while resting. Furthermore, it decreases swelling after surgery despite lacking anti-inflammatory functions. Paracetamol effects its analgesic action in the central nervous system by activating the descending serotonergic pathway which then blocks nociceptive sensation transmission (Amerongen G. et al., 2013). Paracetamol taken in the right dosage does not have any side effect but an overdose will lead to hepatic necrosis due to the depleted glutathione and binding of excess reactive metabolite to vital cell constituents. This is treated with methionine and N-acetylcystein. Enoxaparin sodium is a low molecular weight (LMW) heparin anticoagulant (Li A. et al., 2016). It was administered to the patient at 40mg once a day subcutaneously. It prevents deep vein thrombosis because he is at a high risk of developing it due to the total hip replacement surgery. Enoxaparin sodium is administered as a full dose therapy of 1mg/kg every 12 hours which corresponds to the normal anti-factor Xa level in the blood of 0.5-1 unit/ml. However, this varies with some patients who are selectively given a higher dose of 1.5 units/ml due to their large anti-factor Xa concentration of 1.5units/ml. subcutaneous method of administration has a high bioavailability of close to 100%.

Absorption of Enoxaparin sodium occurs rapidly through the subcutaneous route of administration and the rate of absorption is directly proportional to the amount of drug administered. Enoxaparin sodium has a varying duration of action depending on the dose, the patient and the nature of the drug. It is made in an oily vehicle hence its absorption is low (Furie B. 2013). The distribution is also very slow and low because it binds onto plasma albumin for transportation. The mean maximum plasma anti-factor Xa observed after administration is in 3-5 hours. It has a relatively long half-life in the plasma of approximately 3.5 hours after a single subcutaneous dose and 7.5 hours after repeated dose. Enoxaparin sodium is metabolized in the liver by depolymerisation with lower molecular weights and potency. It stays for longer in the body system because it cannot be excreted unmetabolised and renal excretion for both active and inactive fragments represents 40% of the total dose. Enoxaparin sodium ensures that coagulation does not take place in the blood which will lead to deep vein thrombosis and can lead to pulmonary embolism. This is specifically important because Mr. Smirnov has recently been on a long surgical procedure. It has a high anti factor Xa activity and a low anti-factor 11a or anti-thrombin activity. Enoxaparin sodium blocks the ᵞ-carboxylation on factor X and anti-coagulant protein C and S glutamate residues. This results to incomplete coagulation of the metabolically active coagulation agents. Enoxaparin sodium has severe side effects such as increasing the risk of hemorrhaging, active ulceration and angiodysplastic gastrointestinal disease. There are also rare cases of spinal anaesthesia. There is also nausea which the patient is experiencing together with pruritus.

He also used Ondansetron ODT also known as Zofran. His dose was 8mg twice a day. This medication is special and preferably used alone to prevent nausea and vomiting especially after chemotherapy, radiotherapy or surgery. This drug is unique in that it is put on top of the tongue and left to dissolve without being chewed or swallowed (Goldman L. et al., 2016). After it dissolves it is then swallowed with the saliva. It is essential not to get this drug into contact with water or take it with water because there is a risk of severe headache. The dosage is a maximum of 8mg daily as directed by a doctor. The bioavailability varies between 56%-71% this because of the possible first pass effect (Bertram G. 2018). Zofran was orally administered and absorption took place in the stomach. The presence of food in the stomach increases the extent of absorption. Its first effect is felt 30 minutes after intake and its peak plasma time is 2 hours after administration. As Zofran is distributed, 70-76% of it is normally bound on blood protein and there is a distribution volume of averagely 2.2-2.5 L/kg. It undergoes hepatic metabolism through a series of steps like hydroxylation and glucuronide or sulfate conjugation which is facilitated by CYP2D6. The product of metabolism is the inactive form glucuronide conjugate and/or sulfate conjugate. After metabolism Zofran is eliminated either through urine or feces. It has a half-life of 3-7 hours in adults with the number of hours increasing depending on whether the patient has hepatic impairment (Roeckel L. A. et al., 2016). The total body clearance is 600-700mL/min and a renal clearance of 0.26-0.38 L/hr/kg. The primary excretion mode is through urine which accounts for 30-70% while feces accounts for 25% of the excretion.

Zofran usually requires a small quantity of the drug to produce an effective clinical response. It was administered to reduce the frequent vomiting Mr. Smirnov had while taking his medication. It is very selective in its action and acts as an antagonist at a serotonin 5-HT3 receptor. It was established as an anti-emetic due to its ability to antagonize vomiting and retching after surgery and cancer treatment through chemotherapy and radiotherapy. It blocks nausea and vomiting in the central nervous system area of the postrema which is the nucleus tractus solitaries (NTS) (Kharasch E. D. et al., 2015). Here, the vestibular nuclei is the chemoreceptor that detects chemical changes that may trigger the process of vomiting and through the action of serotonin, the upper gastrointestinal tract is triggered by the vagus nerve from the influence of motor and visceral ementic outputs. Zofran is therefore an antagonist to serotonin and blocks the receptor. It also functions by blocking the peripheral nervous terminal of the vagus nerve. Its side effects include pruritus and constipation which Mr. Smirnov is already experiencing and others like headache, fatigue, dizziness, fever and gynecologic disorder. It does not affect dopamine receptors hence there is no extrapyramidal symptoms. Diclofenac is a non-steroidal anti-inflammatory drug that has analgesic, antipyretic and anti-inflammatory properties. It was orally administered with a dose of 50mg three times a day. It is useful in pain reduction, inflammation and fever (Dinarallo C. L. et al., 2012). Its bioavailability is 50% due to the first pass effect. Food presence in the gastric tract does not affect its absorption. In its distribution it is bound onto serum protein albumin over the concentration range 0.15-1.5 mg/mL with a distribution volume of 1.4 L/kg. It diffuses in and out of the synovial fluid when there is a concentration gradient (Goter A. L. et al., 2012). It is metabolized and its metabolites are found in the plasma and urine and include 4’-hydroxydiclofenac, 5’-hydroxydiclofenac and 3’-hydroxydiclofenac whose formation is mediated by CYP2C9 which have weak pharmacologic activity. Both diclofenac and its metabolites undergo glucuronidation or sulfation and are biliary excreted. The glucuronide and sulphate are excreted through urinary and biliary excretion and there is very little and mostly no unchanged diclofenac. It has a half-life of approximately 2 hours (Bertram G. 2018).

Diclofenac is a non-selective cyclo-oxgenase 1 and 2 inhibitor. It inhibits prostaglandin synthesis hence reduces arachidonic acid release and enhances its uptake and therefore inhibits two pathways, the cyclooxygenase and lipooxygenase pathway (Glyn-Jones S. et al., 2015). By inhibiting prostaglandin synthesis in peripheral tissues, inflammation is reduced because the inflammation agents are not being synthesized. Diclofenac is always administered for a short period of time due to the several side effects that accompany it such as headaches, nausea, gastrointestinal tract ulcerations and bleeding and rashes (Goldmam L. et al., 2016). Mr. Smirnov is already experiencing persistent nausea, Diclofenac and anticoagulants have a synergistic effect on bleeding and the concomitant use has the increased risk of bleeding. Lactulose is a type of artificial disaccharide of galactose and fructose solution that cannot be broken down and is administered to reduce the amount of ammonia in blood and to assist in constipation (Kalunian K. C. 2016). It was prescribed for the patient to take orally 15ml of it twice a day. When administered orally it takes a longer action time of about 24-48 hours. Its absorption is very minimal and its distribution is within the lumen of the colon. Lactulose is metabolized is by colonic bacteria fermentation and as fecal matter is passed out the unabsorbed part is excreted too while the minimally absorbed part is excreted in urine. It has a half-life of 1.7 – 2 hours. The beta glycosidic linkage of the sugar is resistant to hydrolysis by the digestive enzymes making it effective in treatment. Once taken lactulose is fermented by colonic bacteria leading to a change in the ecosystem of the bacteria through production of lactic acid and small chain fatty acids as a product of the fermentation. The osmotic pressure in the intestinal lumen increases and water moves from the neighboring cells into the lumen and the fecal volume is increased due to due to the water present in the lumen and peristalsis is stimulated hence bowel movement occurs (Elina T. et al., 2012). This is needed to enable Mr. Smirnov to pass his bowel to prevent obstruction which can lead him back into the operation table. It rarely has side effects but its precaution should be taken with lactose intolerant and the diabetic.

A nurse has important responsibilities during the administration of drugs to patients in wards especially those from surgery. The nurse is required to ensure that it is actually Mr. Smirnov taking the medication by checking formal identification documents and physical confirmation by either using technology or confirming with the patient (Di F. et al., 2014). The nurse should confirm that it is actually the right medication being administered by looking at the doctor’s notes and the patient’s chart and also ensuring the dose is correct. This is important because a wrong prescription can cause severe anaphylaxis or even be lethal due to the sensitivity of Mr. Smirnov’s age. Nurses that are not independent prescribers are not authorised the use of medicines outside beyond their authorisation (NMC, 2017). Furthermore the nurse is in-charge of making sure the correct route of administration of the drug is used and should not go by the patient’s request (CQC 2015). Mr. Smirnov may shy away from painful routes of administration like IV, which are important for his quick recovery. The nurse is also required to confirm the last time Mr. Smirnov took his medication to determine if it is appropriate for the next dose to be taken (Bhatt D. L., 2016). This is to avoid the build-up of these drugs to toxic levels in the blood and tissues. The nurse is then required to ensure the medication is taken by the patient and should document the information on the patient’s file then not down the immediate response and later monitor the patient further. The patient was under a medication regime of 6 drugs concurrently. Morphine was essential for severe pain the patient felt while moving. It was administered in the appropriate universal dosage however its side effects brought even more discomfort to the patient such as pruritus. Stronger analgesics would further weaken the patient hence morphine was the most appropriate drug for this situation. Paracetamol was efficient for the mild pain experienced when the patient was immobile and the dosage was in the right amount hence no probable side effects were experienced. Enoxaparin sodium anticoagulant was an efficient prophylaxis method to ensure there are no complications post-surgery however the few side effects that were experienced such as pruritus and gastrointestinal pain (Olsen A. M. S. et al., 2015).

The compression stockings were essential in ensuring there was no blood accumulation in the lower limbs which may have accelerated clot formation and led to deep vein thrombosis and further pulmonary embolism. Ondansetron was prescribed to reduce the side effects of other medication such as morphine with nausea. However, it was prescribed in the wrong situation because there was no chemotherapy or radiotherapy and the patient was just from a surgery (Bertram G. 2018). It worsened the pruritus and the constipation that the patient was already experiencing and a better alternative should have been sought especially since the patient is neither diabetic nor lactose intolerant. Diclofenac was administered as an analgesic and to prevent any probable inflammation that may occur in the body. However, as a non-selective COX 1 and 2 inhibitor it caused gastrointestinal ulcerations and more complications that reduced the ability of the patient to manage food which will ultimately prolong recovery period (Olsen A. M. S. et al. 2015). Finally, the lactulose administered was really beneficial to the patient as it reduced constipation and bowel movement was facilitated. The routes of administration were determined depending on the physical characteristic of the drug such as ondansetron which is only orally administered. The speed of absorption is also considered hence enoxaparin sodium was considered. There was a need to bypass hepatic metabolism hence IV route was used for morphine. The condition of the patient could not allow rectal administration of lactulose hence it was administered orally. Paracetamol was orally administered because IV route would cause further pain and inconvenience to the patient.

Mr. Pasha is an 83 year old living with his son and daughter-in-law who were involved in making decisions concerning his health and the best treatment methods that he could be taken through at his age. He is also of sound mind and is capable of comprehending the doctor’s explanations to understand what he was taken through. There is accountability being held within his medication monitoring by his doctor, his nurse, the head of the ward he is in and there is a legal aspect included in his treatment to ensure all the treatment is done to his best interest. There are several legal, ethical and professional issues that are always considered before medication is administered. The health professionals always have to be sure that what they are doing it with the patient’s best interests at heart and they are accountable for their actions (NMC 2017). The nurse’s pre drug administration assessment is essential to determine if the patient will respond positively to the drug or would develop complications. Peri drug administration assessment is essential to ensure that all the medication is taken and right administration routes are used (Alexander S. P. H. et al., 2015). Post administration assessment is for monitoring the working of the drug, to ensure the patient is still safe and to ensure no complications develop. Pain assessment is key because it determines the management method that would be taken after. The nurse is present to ensure that there is physical confirmation and to confirm the eligibility of the patient. The nurse is also crucial to perform the assessment of the numerical rating scale (NRS) and to use the ACVPU tool to determine the pain score of the patient (Correia M. A. et al. 2015). Later the nurse is key in ensuring the right management method is used such as morphine for severe pain and paracetamol for mild pain as per the assessment conclusion.

Mr. Smirnov is experiencing moderate pain as per the scale reading during movement and mild pain while resting. A surgery involves making incisions through the tissues while damaging some of them and putting the tissues back together using stitches. Despite being under anesthesia there is tissue damage that has occurred which would generate action potential for the nociceptive receptors post operation. The pain is mostly nociceptive and further classified as deep somatic pain because it involves the bones and the muscles together with tendons. The patient also experiences peripheral neuropathic pain from the nerves around the joint replaced (Christopoulos A. 2014). Pain management is a very important aspect of treatment and should always be addressed when the patient raises a flag. Pain from the involved muscles, nerves and joints will cause weakness over time and the patient becomes immobile which is worse. The endocrine system is affected due to the access catecholamine and glucocorticoid produced as the body tries to control the pain (Wilser J. W. et al., 2014). The cardiovascular system is also affected as the sympathetic action is causing increased heart rate which leads to tachycardia and hypertension which is dangerous (Olson E. N. 2014). The immune system also tries to reduce the pain which may cause inflammation to the affect parts. Which may further interfere with pain control. Side effects identification is important so as to differentiate it from the sickness of the patient. Side effects are those that arise after medication is administered and have been identified by the drug manufacturers to occur after the drug is given. It can be a headache that wasn’t present before or a rash (Kalunian K. C. 2016). Some side effect manifest as allergies hence it is important to always have the patient’s medical history and study before administering drugs. Communication with the patient will also assist in identifying side effects missed. They are controlled by identifying better drugs with less complications or using countering drugs that lack any further complications.

Conclusion

In conclusion, post-operative pain management is important but should be approached carefully with the right medication for the patient to avoid further pain and to accelerate recovery (Bertram G. 2018). Mr. Pasha was given morphine for moderate pain management, paracetamol and diclofenac for mild pain management. Post operational complications were avoided by using enoxaparin sodium to prevent deep vein thrombosis and his side effects were managed by ondansetron and lactulose.

REFERENCES

Amerongen G., Siebanga P., M. L. Kam, J. L. Hay and G. J. Groeneveld, 2018 European Journal of Pain: Effect Profile of Paracetamol, ∆9-THC and promethazine using an evolked pain test battery in healthy subjects.

Bair M. J., Robinson R. L., Katon W. and Kroenke K. 2013. Depression and pain comorbidity.

Bhatt D. L., Mehta C. 2016. Clinical trials series: Adaptive designs for clinical trials. N Engl J Med;375:65.

Catterall W. A., Swanson T. M. 2015. Structural basis for pharmacology of voltage-gated sodium and calcium channels. Mol Pharm ;88:141.

Christopoulos A. 2014. Advances in G protein-coupled receptor allostery: From function to structure. Mol Pharmacol ;86:463.

Correia M. A., Hollenberg P. F. 2015. Inhibition of cytochrome P450 enzymes. In: Ortiz de Montellano P (editor): Cytochrome P450: Structure, Mechanism and Biochemistry, 4th ed. Springer International.

Dar A. C., Shokat K. M. 2011. The evolution of protein kinase inhibitors from antagonists to agonists of cellular signaling. Ann Rev Biochem ;80:7069.

Dinarello C. A., Simon A., Van der Meer J. W. 2012. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov.

Downing N. S. 2012. Regulatory review of novel therapeutics—Comparison of three regulatory agencies. N Engl J Med ;366:2284

Elina Tiippana, Katri Hmumnen, Vesa Kontinen and Eija Kalso, 2012. Basic and Clinical Pharmacology and Toxicology : The Effect of Paracetamol and Tropicetron on Pain.

Emma J. Turtle, James W. Dear, David J. Webb, 2013. British Journal of Clinical Pharmacology: The Effect of Blood Pressure on Hypertensive and Non-hypertensive Subjects.

Esseltine J. L., Scott J. D., 2013. AKAP signaling complexes: Pointing towards the next generation of therapeutic targets? Trends Pharmacol Sci 2013;34:648.

Gisele Pickering, Fares Moustafa, Stephanie Desbrandes, J. Michel Cardot, Delphine Roux and Claude Dubray, 2011. Fundamental and Clinical Pharmacology: Paracetamol and Opioid Pathways.

Glyn-Jones, S., Palmer, A.J.R., Agricola, R., Price, A.J., Vincent, T.L., Weinans, H. and Carr, A.J., 2015. Osteoarthritis. The Lancet, 386(9991), pp.376-387.

Gotter A. L. 2012. International Union of Basic and Clinical Pharmacology. Orexin receptor function, nomenclature and pharmacology. Pharmacol Rev;64:389.

Jan L. Y., Jan Y. N. 2012. Voltage-gated potassium channels and the diversity of electrical signalling;590:2591

January, Craig T., L. Samuel Wann, Joseph S. Alpert, Hugh Calkins, Joaquin E. Cigarroa, Joseph C. Cleveland, Jamie B. Conti et al. "2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society." Journal of the American College of Cardiology 64, no. 21 (2014): e1-e76.

Kuntheavy Ing Lorenzini, Marie Besson, Youssef Daali, Denis Salomon, Pierre Dayer, Jules Desmeules, 2011. Basic and Clinical Pharmacology and Toxicology: Peripheral Supra-Additive Anti-hyperalgesic Effect of Paracetamol-Ketorolac Combination.

Liu, X.Y., Liu, Z.C., Sun, Y.G., Ross, M., Kim, S., Tsai, F.F., Li, Q.F., Jeffry, J., Kim, J.Y., Loh, H.H. and Chen, Z.F., 2011. Unidirectional cross-activation of GRPR by MOR1D uncouples itch and analgesia induced by opioids. Cell, 147(2), pp.447-458.

Michael Faure, Gisele Pickering, Fabienne Commun, Elisabeth Carrier de Boissy, Ghislaine Roche, Thierry Mom, Estelle Simen, Claude Dubray, Alain Eschalier and Laurent Gilain,2011. Fundamental and Clinical Pharmacology: Tropisetron and Paracetamol Association in Post-Operation Patients.

Munden, L.M., 2017. The covert administration of medications: legal and ethical complexities for health care professionals. The Journal of Law, Medicine & Ethics, 45(2), pp.182-192.

Olsen, A.M.S., Gislason, G.H., McGettigan, P., Fosbøl, E., Sørensen, R., Hansen, M.L., Køber, L., Torp-Pedersen, C. and Lamberts, M., 2015. Association of NSAID use with risk of bleeding and cardiovascular events in patients receiving antithrombotic therapy after myocardial infarction. Jama, 313(8), pp.805-814.

Percope de Andrade M. A. 2015. Supplementary methods in the non-surgical treatment of osteoarthritis: The Journal of Arthroscopic and Related Surgery.

Roeckel, L.A., Le Coz, G.M., Gaveriaux-Ruff, C. and Simonin, F., 2016. Opioid-induced hyperalgesia: cellular and molecular mechanisms. Neuroscience, 338, pp.160-182.

Samuelson, B.T. and Cuker, A., 2017. Measurement and reversal of the direct oral anticoagulants. Blood reviews, 31(1), pp.77-84.

Spahn, V., Del Vecchio, G., Labuz, D., Rodriguez-Gaztelumendi, A., Massaly, N., Temp, J., Durmaz, V., Sabri, P., Reidelbach, M., Machelska, H. and Weber, M., 2017. A nontoxic pain killer designed by modeling of pathological receptor conformations. Science, 355(6328), pp.966-969.

Volkow, N.D. and McLellan, A.T., 2016. Opioid abuse in chronic pain—misconceptions and mitigation strategies. New England Journal of Medicine, 374(13), pp.1253-1263.

Wisler, J.W., Xiao, K., Thomsen, A.R. and Lefkowitz, R.J., 2014. Recent developments in biased agonism. Current opinion in cell biology, 27, pp.18-24.