Tài liệu CLINICAL PHARMACOLOGY 2003 (PART 19) pdf

SECTION 4 NERVOUS SYSTEM This page intentionally left blank 17 Pain and analgesics But pain is perfect misery, the worst Of evils, and, excessive, overturns All patience. (John Milton, 1608-1674, Paradise Lost) SYNOPSIS One of the greatest services doctors can do their patients is to acquire skill in the management of pain. • Pain: the phenomenon of pain; clinical evaluation of analgesics; choice of analgesics; treatment of pain syndromes; spasm of smooth and striated muscle; neuralgias; migraine • Drugs in palliative care: symptom control; pain • Narcotic or opioid analgesics: agonists, partial agonists, antagonists; morphine and other opioids; classification by analgesic efficacy; opioid dependence; opioids used during and after surgery; opioid antagonists; • Non-narcotic analgesics (NSAIDs): see Ch. 15 tissue damage, or described in terms of such damage. 1 It is mediated by specific nerve fibres to the brain where its conscious appreciation may be modified by various factors. The word 'unpleasant' comprises the whole range of disagreeable feelings from being merely inconve- nienced to misery, anguish, anxiety, depression and desperation, to the ultimate cure of suicide. 2,3 • Analgesic drug: a drug that relieves pain due to multiple causes, e.g. paracetamol, morphine. Drugs that relieve pain due to a single cause or specific pain syndrome only, e.g. ergotamine (migraine), carbamazepine (neuralgias), glyceryl trinitrate (angina pectoris), are not classed as analgesics; nor are adrenocortical steroids that suppress pain of inflammation of any cause. • Analgesics are classed as narcotic (which act in the central nervous system and cause drowsiness, i.e. opioids) and non-narcotic (which act chiefly peripherally, e.g. diclofenac). • Adjuvant drugs are those used alongside analgesics in the management of pain. They are not themselves analgesics, though they may modify the perception or the concomitants of pain that make it worse (anxiety, fear, Pain Pain is an unpleasant sensory and emotional experience associated with actual or potential 1 Merskey H et al 1979 Pain terms: a list with definitions and notes on usage. Pain 6: 249. 2 Melzack R, Wall P 1982 The challenge of pain. Penguin, London. 3 Loeser J D, Melzack 1999 Pain: an overview. Lancet 353:1607. 319 17 PAIN AND ANALGESICS depression), 4 e.g. psychotropic drugs, or they may modify underlying causes, e.g. spasm of smooth or of voluntary muscle. The general principle that the best treatment of a symptom is removal of its cause applies. But this is often impossible to achieve and symptom relief of pain by analgesic drug is required. Pain is the most common symptom for which patients see a doctor. The complaint does not mean that an analgesic is needed. To manage the pain, the doctor needs to know what is happening to the patient in mind and body. Optimal management of pain requires that the clinician should have a conceptual framework for what is happening to the patient in mind and body. • Acute pain is managed primarily (but not invariably) by analgesic drugs. • Chronic pain often requires adjuvant drugs in addition as well as nondrug measures. Analgesics are chosen according to the cause of pain and its severity. Phenomenon of pain An understanding of the phenomenon of pain ought to accommodate the following points: • Pain can occur without tissue injury or evident disease and can persist after injury has healed. • Serious tissue injury can occur without pain. • Emotion (anxiety, fear, depression) is an inseparable concomitant of pain and can modify both its intensity and the victim's behavioural response. • There is important processing of afferent nociceptive (see below) and other impulses in the spinal cord and brain. Appreciation that pain is both a sensory and an emotional (affective) experience has allowed clini- cians to realise that to meet a complaint of pain automatically with a prescription alone is not an appropriate response, for 'There is always more to analgesia than analgesics'. 5 Pain that is not the subject of an analysis by the clinician (and explana- tion to the patient) may be inadequately relieved because of lack of understanding. It is a justified and shaming criticism if doctors do not provide adequate relief of severe pain (postsurgical, pallia- tive care of advanced cancer) by bad choice and by overusing and, also important, underusing drugs, and by defective relations with their patients. THE VARIOUS ASPECTS OF PAIN Pain is not simply a perception, it is a complex phenomenon or syndrome, only one component of which is the sensation actually reported as pain. Pain has four major aspects present to varying extent in any one case: Nociception 6 is a consequence of tissue injury (trauma, inflammation) causing the release of chemical mediators which activate nociceptors, defined as receptors that are capable of distinguish- ing between noxious and innocuous stimuli in the tissue. That said, it is widely assumed that there is no specific single histological structure that is a noci- ceptive receptor, but that free unmyelinated termi- nals in skin, muscle, joints and viscera are activated by noxious stimuli and transmit information by thin myelinated (A-delta) and nonmyelinated (C) fibres to the spinal cord and brain. Thus nociception is not, for example, due to overstimulation of touch or other receptors. A number of receptors, identified by anatomical, electrophysiological and pharmaco- logical means, have been associated with nocicep- tors, and include acetylcholine, prostaglandin E, adrenergic, 5-hydroxytryptamine, glutamine, brady- kinin, opioid and adenosine. The ligands for these receptors may be released in the periphery from neurones or be of non-neuronal origin. Pain perception is a result of nociceptive input plus a pattern of impulses of different frequency and intensity from other peripheral receptors, e.g. heat, 4 Tricyclic antidepressants may reduce morphine requirement in palliative care without noticeably altering mood. 5 Twycross R G 1984 Journal of the Royal College of Physicians of London 18: 32. 6 Latin: noxa: injury. 320 17 and mechanoreceptors whose threshold of response is reduced by the chemical mediators. These are processed in the brain whence modulating inhibi- tory impulses pass down to regulate the continuing afferent input. But pain can occur without nocicep- tion (some neuralgias 7 ) and nociception does not invariably cause pain; pain is a psychological state, though most pain has an immediately antecedent physical cause. Suffering is a consequence of pain and of lack of understanding by patients of the meaning of the pain; it comprises anxiety and fear (particularly in acute pain) and depression (particularly in chronic pain), which will be affected by patients' persona- lities, and their beliefs about the significance of the pain, e.g. whether merely a postponed holiday, or death, or a future of disability with loss of indepen- dence. Depression makes a major contribution to suffering; it is treatable, as are the other affective concomitants of pain. Pain behaviour comprises consequences of the other three aspects (above); it includes behaviour that is interpreted by others as signifying pain in the victim, e.g. such immediate and obvious aspects as facial expression, restlessness, seeking isolation (or company), medicine-taking, as well as, in chronic pain, the development of querulousness, depres- sion, despair and social withdrawal. It is thus useful to distinguish between acute pain (an event whose end can be predicted) and chronic pain (a situation whose end is commonly unpredictable, or will only end with life itself). The clinician's task is to determine the signifi- cance of these items for each patient and to direct therapy accordingly. Analgesics may, but not neces- sarily will, be the mainstay of therapy; adjuvant (nonanalgesic) drugs may be needed, as well as nondrug therapy (radiation, surgery). TYPES OF PAIN Acute pain (defined as of < 3 months duration) is 7 Neuralgia is pain felt in the distribution of a peripheral nerve. PHENOMENON OF PAIN transmitted principally by fast conducting A-delta fibres (but to a lesser extent involves slow conduct- ing type C fibres) and has major nociceptive input (physical trauma, pleurisy, myocardial infarct, perforated peptic ulcer). Patients perceive it as a transient, though sometimes severe threat and they react accordingly. It is a symptom that may be dealt with unhesitatingly and effectively with drugs, by injection if necessary, at the same time as the causative disease is addressed. The accompanying anxiety will vary according to the severity of the pain, and particularly according to its meaning for the patient, whether termination with recovery will soon occur, major surgery is threatened, or there is prospect of death or invalidism. The choice of drug will depend on the clinician's assessment of these factors. Morphine by injection has retained a pre- eminent place for over 100 years because it has highly effective antinociceptive and anti-anxiety effects; modern opioids have not rendered morphine obsolete. Neuropathic pain follows damage to the nervous system. Acute pain without nociceptive (afferent) input (some neuralgias) is less susceptible to drugs unless consciousness is also depressed, and any frequently recurrent acute pain, e.g. trigeminal neuralgia, poses management problems that are more akin to chronic pain. Chronic pain is transmitted principally by slow conducting type C fibres (but to a lesser extent by fast conducting A-delta fibres). It is better regarded as a syndrome 8 rather than as a symptom (see above) for it is a collection of disparate pains of long duration, often sharing common emotional and behavioural aspects. It presents a depressing future to the victim who sees no prospect of release from suffering, and poses for that reason long-term management problems that differ from acute pain. Suffering and affective disorders can be of over- riding importance and the consequences of poor management may be prolonged and serious for the patient. Analgesics alone are often insufficient and 8 A set of symptoms and signs that are characteristic of a condition though they may not always have the same cause (Greek: syn: together, dramein: to run). 321 17 PAIN AND ANALGESICS adjuvant drugs as well as nondrug therapy gain increasing importance. Although dependence is less of a problem than might be feared, continuous use of high efficacy opioids, e.g. morphine, pethidine, is generally is best avoided in chronic pain (except that of palliative care). But the lower efficacy opioids (codeine, dextropropoxyphene) may often be needed and used. Sedation should be avoided and therapy should be oral if possible; regimens should be planned to avoid breakthrough pain. Antidepressants can often be useful. Sedative-hypnotic drugs, e.g. benzo- diazepines, may be needed for anxiety but may induce depression. Chronic pain syndrome is a term used for persistence of pain when detectable disease has disappeared, e.g. after an attack of low back pain. It characteristically does not respond to standard treatment with analgesics. Whether the basis is neurogenic, psychogenic or sociocultural it should not be managed by intensifying drug treatment. Opioid analgesics, which may be producing depen- dence, should be withdrawan and the use of psycho- tropic drugs, e.g. antidepressants or neuroleptics, and nondrug therapy, including psychotherapy, should be considered. Transient pain is provoked by activation of noci- ceptors in skin or other tissues in the absence of tissue damage. It has evolved to protect humans from physical damage from the environment or excessive stressing of tissues. It is a part of normal life and not a reason to seek medical help. Never- theless, it is partly through the production of transient pain in physiological experiments that present concepts of pain have evolved. MECHANISMS OF ANALGESIA Endogenous opioid neurotransmitters in the spinal cord and brain constitute a pain inhibitory system; they are activated by nociceptive and other inputs (including treatments such as transcuta- neous nerve stimulation, and acupuncuture) and mediate their effects through specific receptors. Activation of opioid receptors prevents the release of substance P (a neurotransmitter and local hormone involved in pain transmission) with the result that pain transmission is inhibited. Several types of receptor have been recognised, principally: (j, (mu), 5 (delta) and K (kappa) receptors for which the endo- genous ligands respectively are: endomorphins, met- encephalin and dynorphins. Synthetic opioids produce analgesia by simulat- ing the body's natural opioids and the existence of different types of receptor explains their varying patterns of actions. Definition of these receptors and their subdivisions offers hope for the design of new selective high-efficacy analgesics free from the disadvantages of the existing opioids. Naloxone, the competitive opioid antagonist, binds to and blocks all opioid receptors but exerts no activating effect. Naloxone has particularly high affinity for the (0-receptor; it worsens (dental) pain, an effect that may be explained by blocking access of endogenous opioids to their receptor(s). 9 It does not induce hyperalgesia or spontaneous pain because the opioid paths are quiescent until activated by nociceptive and other afferent input. In addition to these opioid mechanisms, non- opioid mediated pathways, e.g. serotonin, are important in pain. There is suggestion that opioid mechanisms are more important in acute severe pain, and nonopioid mechanisms in chronic pain, and that this may be relevant to choice of drugs. NSAIDs. When a tissue is injured (from any cause), or even merely stimulated, prostaglandin synthesis in that tissue increases. Prostaglandins have two major actions: they are mediators of inflammation and they also sensitise nerve endings, lowering their threshold of response to stimuli, mechanical (the tenderness of inflammation) and chemical, allowing the other mediators of inflammation, e.g. histamine, serotonin, bradykinin, to intensify the activation of the sensory endings. Plainly, a drug that prevents the synthesis of prostaglandins is likely to be effective in relieving pain due to inflammation of any kind, and this is indeed how aspirin and other nonsteroidal anti- inflammatory drugs (NSAIDs) act. This discovery was made in 1971, aspirin having been extensively 9 Naloxone also appears to cause pyrovats (practitioners of religious firewalking ceremonies) to quicken their pace over the hot coals. 322 CLINICAL EVALUATION OF ANALGESICS 17 used in medicine since 1899. 10 NSAIDs act by inhibiting cyclo-oxygenase (see p. 280). Thus it is evident that NSAIDs will relieve pain when there is some tissue injury with consequent inflammation, as there almost always is with pain. They also act in the central nervous system (prostaglandins, despite their name, are synthesised in all cells except erythrocytes) and there is probably some central component to the analgesic effect of NSAIDs. But, analgesic and anti-inflammatory effects are not parallel, e.g. aspirin relieves pain rapidly at doses that do not significantly reduce inflammation and the onset of its anti-inflammatory effect at higher doses may be slow. Paracetamol is an effective anal- gesic for mild pain but has little anti-inflammation effect in arthritis, though substantial effect on post- dental extraction swelling. Other NSAIDs show a different mix of action against pain and inflamma- tion (see Ch. 15). Corticosteroids diminish inflammation of all kinds by preventing prostaglandin synthesis (the phospho- lipase A that releases arachidonic acid for such synthesis is inhibited by lipocortin-1 which is produced in response to glucosteroids). Short-term use may be valuable; long-term use poses many problems (see Ch. 34); in general the corticosteroid should be withdrawn after one week if there is no benefit. The pain threshold is lowered by anxiety, fear, depression, anger, sadness, fatigue, or insomnia, and is raised by relief of these (by drug or nondrug measures) and by successful relief of pain. Since emotion is such an important factor in pain, it is no surprise that placebo tablets or injections alleviate pain but with the added disadvantage that they rapidly lose effect with repetition. The importance of the meaning of pain to its victim is illustrated by injuries of war and of civilian life: 10 Propagandists for complementary (alternative) medicine allege that conventional scientific medicine will not recognise any therapy, e.g. complementary medicine, unless its mode of action is known. This is untrue. Validated empirical observation, i.e. scientific evidence, is and always has been accepted. To the wounded soldier who had been under unremitting shell fire for weeks, his wound was a good thing (it meant the end of the war for him) and was associated with far less pain than was the case of the civilians who considered their need for surgery a disaster. 11 The desire for analgesics has been found to be less amongst victims of battle injuries than amongst comparable civilian injuries. On the other hand, morphine has been found to be relatively ineffec- tive against experimental pain in man, probably because it acts best against pain that has emotional significance for the patient. New analgesics have been successfully developed by animal testing, possibly because the emotional response to experimental pain in an animal is akin to the human response to disease or accidental injury. This emotional response does not generally occur in a subject who has volunteered to undergo laboratory experiments that can be stopped at any time, and it probably accounts for the fact that a placebo gives relief in only 3% of these cases. Clinical evaluation of analgesics Therapeutic trials in acute pain are often conducted on patients who have undergone abdominal surgery or third molar tooth extraction, and in chronic pain on chronic rheumatic conditions. Only the patients can say what they feel and pain is best measured by a questionnaire or by a visual analogue scale; this is a line, 10 cm long, one end of which represents pain 'as bad as it could possibly be' (which patients identify as 'agonising') and the other end 'no pain'; patients mark the line at the point they feel represents their pain between these two extremes. Such techniques are highly reproducible. Since what is being measured is how patients say they feel, the trial must be double-blind. 11 Beecher H K 1957 Pharmacological Review 9: 59. 323 17 PAIN AND ANALGESICS Observers who interrogate the patients for relief (intensity and duration) and adverse effects must be constant and trained. If asked by a personable young woman, a higher proportion of patients (of both sexes) admit to pain relief if the same question is put by a man. Choice of analgesics 12 RANKED BY CLINICAL EFFICACY (see also ranking of opioids, p. 338) Mild pain • Non-narcotic (nonopioid) analgesics or NSAIDs, e.g. paracetamol, ibuprofen, diclofenac. 13 (Ch. 15) Where these fail after using the full dose range, proceed to drugs for: Moderate pain • Narcotic (opioid) analgesics, low-efficacy opioids, e.g. codeine, dihydrocodeine, dextropropoxyphene, pentazocine. • Combined therapy of NSAIDs plus low-efficacy opioid, either as a fixed-dose formulation, which is convenient for acute pain or separately to find the optimum dose of each, which may be preferable for chronic pain though less convenient. Where these fail proceed to drugs for: Severe pain • High-efficacy opioids, e.g. morphine, diamorphine, pethidine, buprenorphine. An added NSAID is useful if there is an additional tissue injury component, e.g. gout, bone metastasis. 12 Based on Twycross R G 1978 In: Saunders Cicely M (ed) The management of terminal disease. Arnold, London. The work of this author contributes much to this chapter. 13 Paracetamol is sometimes not classed as an NSAID because its anti-inflammatory pattern differs substantially from most, i.e. it is central rather than peripheral, as witness its weak anti-inflammatory efficacy in rheumatoid arthritis. Where these fail proceed to drugs for: Overwhelming acute pain • High efficacy opioid plus a sedative/anxiolytic (diazepam) or a phenothiazine tranquilliser, e.g. chlorpromazine, levomepromazine (methotrimeprazine) (which also has analgesic effect). Note: adjuvant drugs (p. 331) may be useful in all grades of pain. COMBINING ANALGESICS Simultaneous use of two analgesics of different modes of action is rational, but two drugs of the same class/mechanism of action are unlikely to benefit unless there is a difference in emphasis, e.g. analgesia and anti-inflammatory action (paraceta- mol plus aspirin), or in duration of action; a patient taking an NSAID with a long duration, e.g. naproxen (used once or twice a day), is benefited by an additional drug of shorter duration for an acute exacerbation, e.g. ibuprofen, paracetamol. A low-efficacy opioid can reduce the effective- ness of a high-efficacy opioid by successfully com- peting with the latter for receptors. Partial agonist (agonist/antagonist) opioids, e.g. pentazocine, will also antagonise the action of other opioids, e.g. heroin, and may even induce the withdrawal syn- drome in dependent subjects. FIXED-RATIO (COMPOUND) COMBINATIONS Large numbers of these are offered particularly to bridge the efficacy gap between paracetamol and morphine. Doctors should consider the formulae of these preparations before using them. Caffeine has been shown to enhance the analgesic effect of aspirin and of paracetamol and to accelerate the onset of effect, but at least 30 mg and probably 60 mg are needed (a cup of coffee averages about 80 mg and of tea averages about 30 mg). Tablets containing paracetamol (325 mg) plus dextropropoxyphene (32.5 mg) (co-proxamol, Distal- gesic), in a dose of 1-2 tablets, provide an effective dose of both drugs and have been extremely 324 PAIN SYNDROMES AND THEIR TREATMENT 17 popular with both prescribers and patients; its popularity may be influenced by a mild euphoriant effect of the opioid, to which dependence can occur. A major concern is that in (deliberate) overdose death may occur within one hour due to the rapid absorption of the dextropropoxyphene, and combination with alcohol appears seriously to add to the hazard. We do not attempt to rank the many preparations available because comparative evidence is lacking. Pain syndromes and their treatment In general, pain (acute or chronic) arising from the somatic structures (skin, muscles, bones, joints) responds to NSAIDs. Acute pain arising from viscera, which is poorly localised, unpleasant, and associated with nausea is best treated with mor- phine but this induces dependence with prolonged use. This distinction is not, of course, absolute and a high-efficacy opioid is needed for severe somatic pain, e.g. a fractured bone. Mild pain from any source may respond to NSAIDs and these should always be tried first. SPASM OF VISCERAL SMOOTH MUSCLE Pain due to spasm of visceral smooth muscle, e.g. biliary, renal colic, when severe, requires a substan- tial dose of morphine, pethidine or buprenorphine. These drugs themselves cause spasm of visceral smooth muscle and so have a simultaneous action tending to increase the pain. Phenazocine and buprenorphine are less liable to cause spasm. An antimuscarinic drug such as atropine or hyoscine may be given simultaneously to antagonise this effect. Prostaglandins are involved in control of smooth muscle and colic can be treated with NSAIDs, e.g. diclofenac, indometacin (i.m., suppository or oral). SPASM OF STRIATED MUSCLE This is often a cause of pain, including chronic tension headache. Treatment is directed at reduc- tion of the spasm in a variety of ways, including psychotherapy, sedation and the use of a centrally- acting muscle relaxant as well as non-narcotic analgesics, e.g. baclofen, diazepam; clinical efficacy is variable (see Other muscle relaxants, p. 357). Local infiltration with lignocaine (lidocaine) is sometimes appropriate. Tizanidine is an cc 2 -adrenoreceptor agonist that may be used to relieve muscle spasticity in multiple sclerosis, spinal cord injury or disease. NEURALGIAS (NEUROPATHIC PAIN) These include postherpetic neuralgia, phantom limb pain, peripheral neuropathies of various causes, central pain, e.g. following a stroke, compression neuropathies, and the complex regional pain syndromes (comprising causalgia, when there is nerve damage, and reflex sympathetic dystrophy, when there is tissue but no nerve injury); they present the most challenging problems. A tricyclic antidepressant and/or an antiepilepsy drug are commonly used in their management; analgesics play a subsidiary part. • Amitriptyline is most frequently used, starting with 10 mg at night increasing to 75 mg. Nortriptyline is better tolerated by some patients. Their general action is to inhibit noradrenaline (norepinephrine) re-uptake by nerve terminals and benefit in neuropathic pain may follow enhanced activity in noradrenergic pain inhibitory paths in the spinal cord. • Gabapentin is the most commonly used antiepilepsy drug in this setting; phenytoin (which raises the threshold of nerve cells to electrical stimulation) or sodium valproate are used for resistant neuralgias. • Transcutaneous electrical nerve stimulation (TENS) helps some sufferers; it may act by promoting the release of endorphins. Ketamine (see p. 353) or lidocaine (lignocaine) (by i.v. infusion) are used in special circumstances. Pain due to nerve compression may be relieved by a corticosteroid injected loccally. • When these measures fail, and an opioid appears necessary, methadone, dextroproxyphene, tramadol and oxycodone are preferred; all possess NMDA-receptor antagonist activity as well as being opioid m-receptor agonists. 325 17 PAIN AND ANALGESICS Trigeminal neuralgia differs from other peripheral neuropathies in its management. The antiepilepsy drug, carbamazepine (p. 417), was accidentally dis- covered to be effective, probably by reducing excit- ability of the trigeminal nucleus. The initial dose should be low, and individuals generally soon learn to alter it themselves during remissions and exacerbations (200-1600 mg/d). It is not used for prophylaxis. Resistant cases may obtain benefit from oxcarbazepine, gabapentin or lamotrigine. Postherpetic neuralgia. The pain of acute herpes zoster (shingles) is mitigated by NSAIDs and opioids (as well as by oral aciclovir started within 48 h of the rash). Whether the incidence of posther- petic neuralgia is reliably reduced by early treatment with an antivirus drug has yet to be proved. Amitrip- tyline is an appropriate initial choice, failing which gabapentin may be used. A topical application of capsaicin, derived from Capsicum spp (pepper and chilli), may be applied as a counter-iritant, although the initial intense burning sensation may limit its use. Conventional analgesics are ineffective. HEADACHE Headache originating inside the skull may be due to traction on or distension of arteries arising from the circle of Willis, or to traction on the dura mater. Headache originating outside the skull may be due to local striated muscle spasm; 14 an anatomical connection, only recently identified, between an extracranial muscle and the cervical dura mater may help to explain headache of cervical origin. Treat- ment by drugs is directed to relieving the muscle spasm, producing vasoconstriction or simply administering analgesics, beginning, of course, with the non-narcotics, e.g. paracetamol, ibuprofen. MIGRAINE The acute migraine attack appears to begin in serotonergic (5-HT) and noradrenergic neurons in the brain. These monoamines affect the cerebral and extracerebral vasculature and also cause release of further vasoactive substances such as histamine, prostaglandins and neuropeptides involved in pain, i.e. there is neurogenic inflammation that can be inhibited by specific antimigraine drugs (below). The migraine aura of visual or sensory disturb- ance probably originates in the occipital or sensory cortex; the throbbing headache is due to dilatation of pain-sensitive arteries outside the brain, including scalp arteries. Identifying and avoiding triggering factors are important. These include stress (exertion, excitement, anxiety, fatigue, anger), food containing vasoactive amines (chocolate, cheese), food allergy, bright lights and loud noise, and also hormonal changes (menstruation and oral contraceptives) and hypo- glycaemia. These precipitants may initiate release of vasoactive substances stored in nerve endings and blood platelets. Many attacks, however, have no obvious trigger. Treatment. A stepped approach to therapy is logical. 15 • The acute migraine attack should be treated as early as possible with an oral dispersible (soluble) analgesic formulation so that it may be absorbed before there is vomiting and accompanying gastric stasis with slow and erratic drug absorption. Aspirin (600 mg) is effective and its antiplatelet action may add to its advantage; paracetamol, ibuprofen and naproxen are alternatives. Metoclopramide or domperidone, dopamine agonists, are useful antiemetics that also promote gastric emptying and enhance absorption of the analgesic. Opioids such as codeine, dihydrocodeine and dextropropoxyphene are not suitable for migraine. • If the oral route is unsuccessful, a rational alternative is to use suppositories of diclofenac 100 mg for pain and domperidone 30 mg for vomiting, although the diarrhoea that may accompany migraine would compromise their efficacy. Efficient use of an analgesic and an antiemetic is adequate for the majority of acute attacks. 14 As in tension headache or frontal headache from 'eyestrain'. 15 British Association for the Study of Headache 2001. http://www.bash.org.uk 326 [...]... importance, except in asthmatics in whom morphine should be avoided anyway because of its respiratory depressant effect Urinary tract Any contraction of the ureters is probably clinically unimportant Retention of urine may occur (particularly in prostatic hypertrophy) due to a mix of spasm of the bladder sphincter and to the central sedation causing the patient to ignore afferent messages from a full... transdermally is also available for pain relief in palliative care • • • • ADJUVANT DRUGS Phenothiazines are antiemetic, antianxiety and sedative agents and they may change the affective response to pain (particularly methotrimeprazine) Tricyclic antidepressants (and perhaps others) have a morphine-sparing effect even in the absence of an effect or mood In selected cases the full range of techniques of... and so morphine is unsuitable for use in tetanus and convulsant poisoning; indeed, morphine can itself cause convulsions Morphine causes antidiuresis by releasing antidiuretic hormone, and this can be clinically important Appetite is lost with chronic use Peripheral nervous system The discovery of opioid receptors is sensory nerves and their inhibiting effect on inflammatory mediators may lead to advances... was treated with continuous subcutaneous heroin (diamorphine) infusion Whilst the randomised controlled trial provides a major basis for therapeutic advance, telling us what generally does happen, the clinical anecdote yet has value, telling us what can happen, and providing examples for us to emulate With intelligent use of drugs, which follows from informed analyses of objectives, doctors can enable... action and respiratory depression (the fatal dose becomes higher), but not to some stimulant agonist effects, e.g constipation and miosis, which persist Opioids that have mixed agonist/antagonist actions (partial agonists) induce tolerance to the agonist but not to the antagonist effects; naloxone (a pure antagonist) induces no tolerance to itself There is a cross-tolerance between opioids (for dependence... extensive presystemic metabolism (mainly conjugation in gut wall and liver) and only about 20% of a dose reaches the systemic circulation; the initial oral dose is about twice the injected dose Given s.c (particularly) or i.m., morphine is rapidly absorbed when the circulation is normal, but in circulatory shock absorption will be delayed and morphine is best given i.v Morphine in the systemic circulation... Maurer D W, Vogel V H 1962 Narcotics and narcotic addiction Thomas, Springfield, Illinois Courtesy of the authors and publisher 30 For a general account, see: Drug Misuse and Dependence — Guidelines on Clinical Management HMSO, London, 1999 31 It has x 2.5 the strength of Methadone Linctus, for cough (yellow or brown); they must not be confused 337 17 PAIN AND A N A L G E S I C S Buprenorphine is an . meaning of the pain; it comprises anxiety and fear (particularly in acute pain) and depression (particularly in chronic pain), which will be affected . Any contraction of the ureters is probably clinically unimportant. Retention of urine may occur (particularly in prostatic hypertrophy) due to