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Question 1
Which of the following statements is correct?
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Opioids comprise products derived from the opium poppy (opiates, eg codeine and morphine) as well as synthetic agonists at the opioid receptor (eg buprenorphine, methadone, and pethidine) and endogenous opioids (endorphins and enkephalins).
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Diphenoxylate is a pethidine derivative, but it does not have useful analgesic effect at usual doses. It is combined with atropine as co-phenotrope for use in the management of diarrhoea.
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Neither of the two mixed agonist–antagonist opioids used in the UK (buprenorphine and pentazocine) is licensed for treating diarrhoea; both have systemic effects. Opioids selected for treating diarrhoea should generally be devoid of systemic effects.
Correct
Although opioids are most often used for managing pain, they are also used for other effects, including suppression of cough, management of diarrhoea, and management of opioid addiction1. Opioids whose activity is confined primarily to the gut (eg diphenoxylate and loperamide) are chosen for controlling diarrhoea, while opioids with long half-lives (eg buprenorphine and methadone) are used for opioid substitution therapy in the management of opioid addiction.
An opioid should not be withheld if it is needed to relieve pain in an opioid-dependent2 person. If opioid abuse3 is continuing the dose of opioid may need to be higher than that used for non-dependent persons, to overcome tolerance4. (However, tolerance can reverse rapidly and a previously tolerated dose might prove hazardous.)
Further, a long-acting opioid can be used for the management of heroin addiction.
Which one of the following statements about gastrointestinal effects of opioids is correct?
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No, nausea and vomiting can occur even if the gastrointestinal tract is bypassed. At least some components of opioid emetic effect rely on direct stimulation of the chemoreceptor trigger zone in the central nervous system, which in turn stimulates the vomiting centre.
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Diarrhoea occurs very rarely during opioid treatment. It occurs most commonly as an opioid withdrawal effect. A far more common side effect of opioids is constipation.
Correct
Constipation can continue to be a troublesome side-effect with long-term use of opioids. Laxative medicines are often required to treat and prevent constipation.
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Pancreatitis is a rare complication of opioid treatment and is unlikely to be the cause of abdominal pain. Abdominal cramps may be the result of pressure in the common bile duct caused by opioid-induced constriction of the opening of the duct (sphincter of Oddi) into the duodenum.
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A wide range of drugs, including antimuscarinics5, antihistamines and dopamine antagonist6 are effective for the treatment of nausea and vomiting caused by opioids.
Which of the following central nervous system adverse effect is most likely with an opioid given by mouth for controlling acute postoperative pain? Choose the single best answer.
Correct
Opioid use is associated with sedation, cognitive impairment and confusion. However, these effects usually diminish on long-term use of an opioid.
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Convulsions rarely occur with therapeutic doses of most of the opioids used for managing pain.
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Hyperalgesia7—an exaggerated response to painful stimuli—is a complication of long-term use of opioid analgesics. It does not occur with short-term use such as in postoperative pain.
4. Pairs of drugs are listed below. Choose a pair most likely to help in dealing with opioid-induced bradycardia and bronchoconstriction.
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Although the antimuscarinic8 effect of hyoscine could help to reverse opioid-induced bradycardia, the absorption of hyoscine butylbromide when given by mouth is inadequate for reliable systemic effect.
As a bronchodilator, ephedrine is less safe than beta2 adrenergic agonists. In practice, drugs with much more specific effect are used to reverse opioid-induced respiratory depression or bronchoconstriction9. Ephedrine was formerly used for its stimulant effect on alpha-adrenergic and beta-adrenergic receptors, to increase blood pressure or for bronchodilation; it also stimulates the respiratory centre.
The calcium-channel blocker verapamil is an antiarrhythmic and antianginal drug. Verapamil is not suitable for reversing opioid-induced bradycardia; it is contraindicated in hypotension and marked bradycardia as it slows conduction through the atrioventricular node.
The management of severe or life-threatening acute asthma involves the use of a systemic corticosteroid, usually prednisolone by mouth or hydrocortisone by intravenous injection. However, a corticosteroid such as dexamethasone is not appropriate treatment for opioid-induced respiratory depression; the specific opioid antagonist10 naloxone is used. Opioid-induced exacerbation of bronchoconstriction11 should first be managed with specific treatment such as oxygen (if necessary) and a beta2 adrenergic agonist such as salbutamol given through a large-volume spacer device or by nebulisation.
Labetalol, with its non-cardioselective beta-blocking activity and some alpha-blocking activity is used for the management of hypertension and even to induce hypotension in some surgical procedures. It is not suitable for managing the cardiovascular effects opioids.
The corticosteroid budesonide has no role in the immediate management of opioid-induced respiratory depression. Exacerbation of bronchoconstriction12 induced by opioids calls for treatment with a beta2 adrenergic agonist such as salbutamol.
Opioid-induced bradycardia responds to treatment with the antimuscarinic13 drug atropine.
Whereas salbutamol does not reverse opioid-induced respiratory depression (a feature of excessive opioid dosage, requiring naloxone), it is effective for the management of bronchoconstriction14, which is often provoked by the release of histamine caused by an opioid.
Adrenaline is a sympathomimetic substance with a range of physiological and dose-related pharmacological effects, including increasing the rate and force of contraction of the heart chambers and relaxation of the bronchioles. However, for the reversal of opioid effects, more specific drugs are preferred.
Naltrexone is not licensed for the management of opioid-induced respiratory depression. Compared to intravenous administration of naloxone, naltrexone by mouth has a longer duration of action and slower onset of effect; therefore, it is not suitable for the treatment of opioid-induced acute respiratory depression.
Three days ago, Dr MA, a 78-year-old retired physicist was started on morphine sulfate tablets 5 mg every 4 hours for severe pain. His pain is now well controlled but he is drowsy and gets a headrush when he sits or stands up. He is especially troubled by opioid-induced pruritus. Which of the following might help relieve the itching?
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Dr MA’s pain is well controlled. Effects such as drowsiness and postural hypotension, as well as pruritus, may diminish with continued use of the opioid. Switching to an NSAID would expose Dr MA to other risks (eg gastroduodenal ulceration and renal impairment) and may compromise pain control.
Correct
Frequent use of an emollient that suits Dr MA will reduce skin dryness and help to reduce itchiness. The pruritus may diminish with continued opioid treatment.
Incorrect
A topical corticosteroid is not appropriate treatment for opioid-induced pruritus. Further, application over large parts of the body may expose Dr MA to the risk of corticosteroid side effects.
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There is little evidence that antihistamines provide effective relief for opioid-induced pruritus. Chlorphenamine is a sedative antihistamine and its use could worsen drowsiness and postural hypotension.
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The risk of pruritus is increased by spinal or epidural use of an opioid, even though a small dose of the opioid is needed.
Sets of withdrawal symptoms are described below. Study each set carefully and select the set most likely to be associated with opioid withdrawal.
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Together with anxiety, depression, fatigue, mood swings and nightmares, these symptoms are those that occur with alcohol withdrawal; convulsions and hallucinations are not typical symptoms of opioid withdrawal.
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Together with vivid dreams, tremor, headache, nausea, and lethargy, these symptoms are those that occur with SSRI withdrawal; headache and paraesthesia (including electric-shock sensation) are not typical symptoms of opioid withdrawal.
Correct
Together with flu-like symptoms, nausea, sweating, anxiety, restlessness, lacrimation, myalgia, arthralgia, and abdominal cramp these features are those that occur with opioid withdrawal.
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Together with agitation, fatigue, malaise, and slower rate of activity, these symptoms are those that occur with cocaine withdrawal; excessive sleep and hunger are not typical symptoms of opioid withdrawal.
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Together with irritability, tremor, muscle pain, and nausea, these symptoms are those that occur with benzodiazepine withdrawal; tinnitus is not a typical symptom of opioid withdrawal.
Which one or more of the following actions help to reduce the risk of opioid dependence?
Correct
The dose of the opioid should be carefully adjusted according to the severity of pain. In the management of acute pain (eg following surgery), the dose should be reduced as pain diminishes.
Correct
Once a dose of opioid has been established for particular circumstances, it is important to arrange to review pain control and the opioid dose.
Correct
The dose of opioid should not be increased if an initial dose has absolutely no effect; in such cases the opioid should be discontinued. Opioids are not effective for certain types of pain and continuing their use despite clear evidence of benefit can lead to opioid dependence and possible misuse.
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The opioid should be selected on the basis of the severity of pain; if a ‘strong’ opioid is required, there should be no hesitation in using it. However, pain control and opioid use should be monitored closely.
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For opioid-responsive pain, the opioid should be taken regularly. Good round-the-clock pain control keeps the patient more comfortable and could even result in a smaller overall demand of opioid than if pain was not properly controlled—poorly managed acute pain can degenerate into persistent pain which might be more difficult to treat.
Which one of the following is likely to increase the risk of constipation when given with an opioid?
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Cefradine is a cephalosporin antibiotic. It can cause diarrhoea and is unlikely to increase the risk of constipation when given with an opioid.
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Ranitidine is a H2 receptor antagonist which reduces secretion of gastric acid and promotes healing of gastric and duodenal ulcers. Ranitidine is not expected to interact with an opioid.
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Cetirizine is a non-sedating antihistamine which blocks the H1 receptor; it is relatively free of antimuscarinic (anticholinergic) activity. Cetirizine is not likely to affect the risk of constipation when taken with an opioid.
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Lamotrigine is an antiepileptic drug; it is also used for managing bipolar disorders. Lamotrigine can cause diarrhoea; it is not expected to interact with opioids to increase the risk of constipation.
Correct
Solifenacin is an antimuscarinic (anticholinergic) urinary antispasmodic; it is used for managing urge incontinence and urinary frequency. Antimuscarinic drugs can increase the risk of opioid-induced constipation and urine retention. Constipation is a common side effect of solifenacin.
Which of the following features is suggestive of an opioid overdose?
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Opioids depress the central nervous system. Opioid overdose is more likely to cause low blood pressure.
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Gooseflesh (or goose-bumps) and shivering are features of opioid withdrawal, not opioid overdose.
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Pupils may be dilated in patients undergoing opioid withdrawal. It is not a feature of opioid overdose.
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Raised body temperature is not a typical feature of opioid overdose. Patients who have taken an excessive dose of opioid are more likely to have a low body temperature.
Correct
Constriction of the pupils is a characteristic feature of opioid overdose. Other important features include respiratory depression and sedation leading to coma.
Ms ZH, aged 26 years, was brought in a comatose state to the accident and emergency department by her companions. Her blood pressure was low and her breathing was slow and shallow. Close questioning of her companions established that she had been abusing opioids for some months and had taken ‘a handful’ of capsules containing oxycodone 3–4 hours ago. Which of the following statements is correct? Choose the single best answer.
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The value of gastric lavage (stomach washout or gastric decontamination) is uncertain and even when it is used, it should be started within an hour of the overdose. Use of the adsorbent, activated charcoal might be of more value, but even so it should ideally be used within an hour of the overdose.
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It may be dangerous to discharge the patient at the first sign of recovery. The specific opioid antagonist naloxone can reverse opioid-induced respiratory depression and increase the level of consciousness. However, the patient needs to be closely monitored for several hours after giving naloxone—as its effects (which are short-lived compared to those of most opioids) wear off, the patient could again lapse into unconsciousness and suffer respiratory depression.
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Convulsions are not a common feature of opioid overdose and it is not necessary to give a drug to prevent fits. Also, a sedative medicine may further complicate the patient’s condition. However, should an epileptic fit occur, specific antiepileptic therapy should be started.
Correct
Intravenous infusion of the opioid antagonist naloxone is appropriate treatment. However it can induce opioid withdrawal effects, which include nausea, vomiting and agitation. Given her history of drug abuse, Ms ZH is likely to suffer withdrawal effects.
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Unlike drugs such as paracetamol and salicylates, which have well-defined ‘toxic dose’, there is no set ‘toxic dose’ for opioids. While a 60-mg dose of morphine sulfate might be dangerous in individuals who are not on opioid treatment or who have received very small doses previously, this dose may be well tolerated by those being treated with relatively high doses of an opioid.
Tramadol accounts for over a third of opioid prescriptions dispensed in the community. Which one or more of the following are likely adverse effects of tramadol:
Correct
Increased perspiration is a well known adverse effect of opioids and is a common effect of tramadol.
Correct
Nausea is a very common adverse effect of tramadol; it is a troublesome short-term side effect of opioids.
Correct
In addition to opioid agonist properties, tramadol also has serotonergic (and noradrenergic) effects. Excessive serotonergic activity when tramadol is combined with an SSRI antidepressant can be dangerous since the combination can, rarely, provoke serotonin syndrome.
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Cimetidine is a liver enzyme inhibitor, but concomitant administration of cimetidine and tramadol does not result in clinically relevant interaction.
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Duodenal ulceration is not a feature of tramadol adverse effects. This side effect is more likely with prostaglandin inhibitors such as aspirin and other NSAIDs.
Following day surgery to repair a nasal injury, Mr JK, a minicab driver has been prescribed a three-day course of co-codamol 30/500 tablets. You are asked to advise him about his medicine. Which of the following is suitable advice?
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Codeine can cause drowsiness and possibly dizziness, impairing the ability to drive. It is wise for Mr JK not to resume his minicab job while he is affected by these side effects. Mr JK may take the tablets 4–6 hourly, up to 4 times per day.
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Mr JK should take the analgesic to control the pain whether the pain occurs during the day or at night. However, it is important that he reduces the dose or stops taking the medicine as the pain diminishes.
Correct
Opioids frequently cause constipation and it would be wise to advise Mr JK of this possibility and suggest appropriate treatment for constipation. Opioids reduce peristalsis and the stool may be hard; fluids and a stimulant laxative may be helpful.
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Each tablet of co-codamol prescribed for Mr JK contains 500 mg paracetamol. Mr JK must not take additional paracetamol otherwise the paracetamol dose would exceed the maximum safe dose. However, if the extra analgesic effect of codeine is no longer required and it is causing troublesome side effects, it would be appropriate to take two paracetamol 500-mg tablets instead of a prescribed dose of co-codamol 30/500.
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It is not necessary to take co-codamol after food since neither paracetamol nor codeine is associated with heartburn or erosion of the duodenal or gastric lining.
Addiction is compulsive substance-seeking behaviour, sometimes also termed ‘substance abuse’; it can involve impaired control over drug use, craving, compulsive use, and continued use despite harm from the substance. Addiction, which can involve genetic, psychosocial and environmental factors, is quite distinct from physical and psychological dependence↩
Dependence is a state that develops as a result of repeated use of a certain chemical substance (eg alcohol, benzodiazepine, opioid, or even medicines for reducing blood pressure). It represents the resetting of homeostasis because of the persisting presence of the chemical substance↩
Any use of an illegal drug or use of a medicine for a non-therapeutic purpose (eg to alter state of consciousness or to seek a ‘high’)↩
Tolerance follows repetitive exposure to a drug, leading to a reduction of the pharmacological effect of that drug↩
Reduction or blocking of the effects of parasympathetic nerves; antimuscarinic effects include dry mouth, difficulty swallowing, blurred vision, confusion, palpitations, constipation, and urine retention↩
A substance that binds to a receptor but produces no effect and inhibits an agonist from binding to the receptor↩
Exaggerated sensitivity to a normally painful stimulus↩
Reduction or blocking of the effects of parasympathetic nerves; antimuscarinic effects include dry mouth, difficulty swallowing, blurred vision, confusion, palpitations, constipation, and urine retention↩
Narrowing of the airways (bronchioles), reducing the flow of air into the lungs; asthma is characterised by bronchoconstriction↩
A substance that binds to a receptor but produces no effect and inhibits an agonist from binding to the receptor↩
Narrowing of the airways (bronchioles), reducing the flow of air into the lungs; asthma is characterised by bronchoconstriction↩
Narrowing of the airways (bronchioles), reducing the flow of air into the lungs; asthma is characterised by bronchoconstriction↩
Reduction or blocking of the effects of parasympathetic nerves; antimuscarinic effects include dry mouth, difficulty swallowing, blurred vision, confusion, palpitations, constipation, and urine retention↩
Narrowing of the airways (bronchioles), reducing the flow of air into the lungs; asthma is characterised by bronchoconstriction↩