Drugs
`
`May 1996, Vol. 51, No. 5 (pp. 701-894)
`ISSN: 0012-6667
`
`FOCUS ON
`Fosinopril, Verapamil, Losartan Potassium,
`Stavudine, Muromonab CD3
`
`LEADING ARTICLE
`
`HIV Protease Inhibitors
`
`REVIEW ARTICLE
`
`Opioid Analgesics
`
`DISEASE MANAGEMENT
`Isolated Systolic Hypertension
`Paediatric Psychopharmacology
`Treatment of Acute Pain in Children
`
`orngting rational drug use
`In Qfsease management
`
`AUCKLAND - CHESTER o FRANKFURT - HONG KONG
`MADRID - MILAN - OSAKA - PARIS - PHILADELPHIA - SYDNEY
`
`Amneal 148
`Amneal v. Endo
`|PR2014—OO36O
`‘
`
`1
`
`

`
` REVIEW ART|CLE oo?销§J733>ii3é'3s3¥éiisllfiiéié
`
`© Adis internationoi Limited. All rights reserved.
`
`Opioid Analgesics
`Comparative Features and Prescribing Guidelines
`
`Nathan 1. Cherny
`
`Cancer Pain and Palliative Medicine, Department of Medical Oncology,
`Shaare Zedek Medical Center, Jerusalem, Israel
`
`Contents
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`1. Basic Principles .
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`1.1 Opioid Receptors .
`1.2 Agonists,PartialAgonists,Agonist—Antagonists and Antagonists .
`1.3 Relative Potency and Equianaigesic Doses .
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`1.4 Dose-Response Reiationship
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`1.5 Opioid Classification .
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`2. Opioid Agonists Conventionaliy Used for Moderate Pain .
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`2.1 Codeine .
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`2.2 Dihydrocodeine
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`2.3 Hydrocodone .
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`2.4 Oxycodone .
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`2.5 Dextropropoxyphene
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`2.6 Tramadol .
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`3. Opioid Agonists Conventionally Used for Severe Pain .
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`3.1 Short HaIf—Life Drugs
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`3.2 Long Ha1f—Life Drugs
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`4. Partial Agonist Opioids .
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`4.1 Buprenorphine
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`5. Mixed Agonist-Antagonist Opioids .
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`5.1 Pentazocine .
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`5.2 Butorphanol
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`5.3 Nciibuphine .
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`6. Principles of Opioid Administration .
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`6.1
`Indications for Opioid Analgesia .
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`6.2 Which Opioid to Use?
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`6.3 Routes of Administration .
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`6.4 Se1ectingaDosage Regimen .
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`6.5 Dosage .
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`7. Adverse Effects of Opioids and Their Management .
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`7.1 Constipation .
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`7.2 Nausea and Vomiting .
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`7.3 Sedation and Cognitive impairment .
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`7.4 Respiratory Depression .
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`7.5 Myocionus .
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`7.6 Urinary Retention .
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`8. Dependence and Addiction .
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`8.1 Physical Dependence .
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`8.2 Addiction .
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`9. Conclusions .
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`2
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`

`
`714
`
`Summary
`
`
`
`Cherny
`
`The term ‘opioid’ is a generic term for naturally occurring, semisynthetic and
`synthetic drugs which combine with opioid receptors to produce physiological
`effects and which are stereospecifically antagonised by naloxone. For clinical
`purposes, opioids can be classified according to their receptor interactions (ago-
`nist, partial agonist, agonist-antagonist and antagonist), the pain intensity for
`which they are conventionally used (moderate or severe), and their half-life (short
`or long). Pure agonists conventionally used for moderate pain, short and long
`half-life pure agonists conventionally used for severe pain, mixed agonist-antag-
`onists and partial agonist opioids are described in detail. The effective clinical
`use of opioid drugs requires familiarity with drug selection, routes of administra-
`tion, dosage guidelines and potential adverse effects. Opioids are unequivocally
`indicated in the management of severe acute pain and moderate to severe pain
`associated with cancer. There is increasing acceptance of the role of opioids in
`the management of recurring acute pain, chronic nonmalignant pain of organic
`origin and severe neuropathic pain. The selection of opioids is influenced by pain
`intensity, pharmacokinetic and formulary considerations, previous adverse ef—
`fects and the presence of coexisting disease. Some patients will require sequential
`trials of several different opioids before a drug which is effective and well toler-
`ated is identified. Opioid agents should be administered by the most comfortable
`and convenient route that meets the specific needs of the patient. The regimen for
`opioid medications should generally provide around-the-clock analgesia with
`provision for rescue doses for the management of exacerbations of the pain not
`covered by the regular dosage. At all times, uncontrolled pain should be addressed
`by gradual increase in the opioid dose until either pain control is achieved or
`intolerable and unmanageable adverse effects supervene. The management of
`pain with opioid analgesics demands frequent patient assessment and a readiness
`to re-evaluate the therapeutic plan in the setting of either inadequate relief or
`adverse effects.
`
`Y
`
`1
`
`i
`
`,
`
`I,
`
`,
`‘
`
`,
`
`The term ‘opioid’ is a generic term for naturally
`occurring,
`semisynthetic and synthetic drugs
`which produce their effects by combining with opi-
`oid receptors and are antagonised by naloxone.
`Drugs whose primary clinical action is the relief of
`
`pain (primary analgesics) are conventionally clas-
`sified on the basis of site of activity on the opioid
`receptors as either opioid or nonopioid analgesics.
`The term opioid is preferred over ‘opiate’ and
`‘narcotic analgesics’. Opiate is a specific term
`which is used to describe drugs (natural and semi-
`
`synthetic) derived from the juice of the opium
`poppy (i.e. morphine is an opiate but methadone,
`which is a synthetic drug, is not).[” The term nar-
`cotic is derived from the Greek word ‘narke’ mean-
`
`ing numbness or torpor; it is an imprecise and pe-
`jorative term that is not useful in a pharmacological
`
`context. Its use with reference to opioids is discour-
`aged.
`
`i. Basic Principles
`
`i.i Opioid Receptors
`
`Opioids are agonists at highly specific receptor
`sites, and there is general agreement on the exist-
`ence of at least 3 types of opioid receptors: it (mu),
`K (kappa) and 5 (delta).[2] These receptors have
`been further subclassified into distinct subtypes: LL;
`and ug, 51 and 52, and K1, K2 and K3. Recently, sev-
`eral of these receptors have been successfully
`cloned.l3]
`
`Table I shows the putative effects mediated by
`the 3 main opioid receptors.[” Opioid receptors are
`found in several areas of the brain, particularly in
`
`© Adis International Limited. All rights reserved.
`
`Drugs 19% May: Si (5)
`
`3
`
`

`
`v
`
`715
`Opioid Analgesics
`
`
`Table I. Responses mediated by opioid receptors
`Receptor
`Response on activation
`it (mu)
`Analgesia, respiratory depression, miosis,
`euphoria, reduced gastrointestinal motility
`Analgesia, dysphoria, psychotomimetic effects,
`miosis and respiratory depression
`Analgesia
`
`K (kappa)
`
`5 (delta)
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`the periaqueductal grey matter, and throughout the
`spinal cord. Supraspinal systems have been de-
`scribed for it}, K3, and 52 receptors while pg, K1,
`and 51 receptors modulate pain at
`the spinal
`level.[2] Recently, opioid receptors have been iden-
`tified in the peripheral nervous system.[4] This ob-
`servation might explain the efficacy of very low
`doses of morphine administered into a site of pe-
`ripheral injury, which has been reported in some
`studies.[5]
`
`i.2 Agonists, Partial Agonists,
`Agonist—Antagonists and Antagonists
`
`On the basis of their interactions with the vari-
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`ous receptor subtypes, opioid compounds can be
`divided into agonist, partial agonist, agonist-
`antagonist and antagonist classes.
`
`1.2. I Pure Agonists
`An agonist is a drug which has affinity for and
`binds to cell receptors to induce changes in the cell
`which stimulate physiological activity. The pure
`agonist opioid drugs have no apparent ceiling ef-
`fect to analgesia. As the dose is raised, analgesic
`effect increases in a log-linear function, until either
`analgesia is achieved or dose-limiting adverse ef-
`fects (such as somnolence, cognitive impairment,
`myoclonus or respiratory depression) occur.
`Efficacy is defined by the maximal response in-
`duced by administration of the active agent. In
`practice, this is determined by the degree of anal-
`gesia produced following dose escalation through
`a range limited by the development of adverse ef-
`fects. Potency, in contrast, reflects the dose : re-
`sponse relationship. Potency is influenced by phar-
`macokinetic factors (i.e. how much of the drug gets
`in to the systemic circulation and then reaches the
`
`receptors) and by the level of intrinsic activity of
`the drug at the receptor level.
`
`I .2.2 Antagonists
`Antagonist drugs have no intrinsic pharmaco-
`logical action but can interfere with the action of
`an agonist. Competitive antagonists bind to the
`same receptor and compete for receptor sites, while
`noncompetitive antagonists block the effects of the
`agonist in some other way.
`
`1.2.3 Mixed Agonist-Antagonists
`The mixed agonist—antagonist drugs produce
`agonist effects at one receptor and antagonist ef-
`fects at another. In contrast to pure agonists, they
`have a ceiling effect for analgesia. Pentazocine is
`the prototype agonist—antagonist: it has agonist ef-
`fects at K receptors, and weak ti antagonist actions.
`Thus, in addition to analgesia, pentazocine may
`produce i<—mediated psychotomimetic effects not
`seen with full or partial it agonists. When a mixed
`agonist—antagonist is administered together with
`an agonist, the antagonist effect at the it receptor
`can generate an acute withdrawal syndrome.
`
`1.2.4 Partial Agonists
`A partial agonist has low intrinsic activity (effi-
`cacy), so that its dose response curve exhibits a
`ceiling effect at less than the maximal effect pro-
`duced by a full agonist. Buprenorphine is the main
`example of a partial agonist opioid. Increasing the
`dose of such a drug above its ceiling level does not
`result in any further increase in response. When a
`partial agonist is administered together with an ag-
`onist, displacement of the agonist can cause a net
`reduction in pharmacological action which may be
`sufficient to generate an acute withdrawal syn-
`drome. This effect is most likely to occur when it
`is administered to a patient receiving high doses of
`a pure agonist.
`
`1.3 Relative Potency and
`Equianalgesic Doses
`
`The relative analgesic potency is the ratio of the
`dose of 2 analgesics required to produce the same
`analgesic effect. By convention the relative po-
`tency of each of the commonly used opioids is
`
`© Adis International Limited. All rights reserved.
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`Drugs 1996 May: 51 (5)
`
`4
`
`

`
`
`
`716
`
`Cherrzy
`
`I(W
`
`$>7’C1€V’0
`
`tl
`
`ti
`
`|wn.A2*-rs-r-i»~nnx~rnn->nnns;\I~:~l_|
`
`Table II. Equinalgesic intramuscular (IM) and oral (PO) doses of opioid analgesics, their elimination half-lives (ti/23) and duration of action
`
`Drug
`Dosea
`ti/as
`Duration of
`IM
`PO
`lM : PO
`(h)
`action
`potency ratio
`(h)
`1 :3
`3-6
`1 :6”
`1 : 1.5
`1 :2
`
`2-3.5
`
`2-3
`3-4
`
`30
`60*’
`200
`30
`100
`7.5
`20°
`300
`10
`60
`4
`
`120
`6
`0.8
`100
`
`: 5
`1
`1 :2
`1 :4
`1 2 10
`1
`: 6
`1 :2
`
`1
`
`: 1.2
`
`1
`
`: 3
`
`Morphine
`
`10
`
`130
`15
`
`1.5
`10°
`75
`1
`5
`2
`0.19
`100
`
`2-4
`Codeine
`2-4
`Oxycodone
`2-4
`Propoxyphene
`2-4
`2-3
`Hydromorphone
`4-8
`15-20
`Methadone
`2-4
`2-3
`Pethidlne (meperidine)
`3-4
`2-3
`Oxymorphone
`3-4
`0.05“
`Diamorphine (heroin)
`4-8
`12-16
`Levorphanol
`1-3'
`1-2‘
`Fentanyl
`4-6
`3-4
`Tramadol
`4-6
`3
`Phenazocine
`6-9
`2-3
`0.4
`Buprenorphine
`3-4
`2-3
`35
`Pentazocine
`Nalbuphine
`10
`5
`3-6
`
`Butorphanol
`19
`25-359
`4-69
`a Equivalent to IM morphine 10mg.
`b Derived from single—dose study.
`c Derived from single-dose study. At steady-state, potency relative to morphine is probably 1-3 : 10 (see text).
`d Rapidly biotranstormed to morphine and acetyl-morphine (see text).
`e Empirically: transdermal fentanyl 100 pg/h = lM morphine 2-4 mg/h.
`f
`Single-dose data. Continual infusion produces lipid accumulation and prolonged terminal excretion.
`g Transnasal relative potency, ti/2;; and duration of action equivalent to parenteral morphine.
`
`based upon a comparison with 10mg of parenteral
`morphine.[53 Data from single dose and repeated
`dose studies in patients with acute or chronic pain
`have been used to develop an equianalgesic dose
`table (incorporated in table II) that provides guide-
`lines for dose selection when the drug or route of
`administration is changed.
`
`limit on the useful dose of a pure opioid agonist.
`Thus, the efficacy of any particular drug in a spe-
`cific patient will be determined by the degree of
`analgesia produced following dose escalation to
`intolerable and unmanageable adverse effects.[7]
`
`1.5 Opioid Classification
`
`1.4 Dose—Response Relationship
`
`The pure agonist opioid drugs appear to have
`no clinically relevant ceiling effect to analgesia.
`As the dose is raised, analgesic effects increase
`as a log-linear function until either analgesia is
`achieved or dose—limiting adverse effects super-
`venem In practice, however, the appearance of ad-
`verse effects, including confusion, sedation, nau-
`sea, vomiting or respiratory depression, imposes a
`
`For clinical purposes, opioids can be classified
`according to their receptor interactions, the pain
`intensity for which they are conventionally used,
`and their half—life (table 111). The classification of
`
`opioids according to the pain intensity for which
`they are conventionally used has replaced the divi-
`
`sion of opioid agonists into weak versus strong opi-
`oids, incorporated into the original ‘analgesic lad-
`der’ proposed by the World Health Organizationflgl
`
`© Adis International Limited. All rights reserved.
`
`Drugs i996 May; 51 (5)
`
`
`
`
`
`
`
`_...WV,._.._._..._...,,_—-.....-.—......-...-..~——_..»——.——--.4~——’v—m~--———-»~-v-——-«-—~*--v------—"---**""""'-'°"”“““"""'"'“"""“‘”“"
`
`
`
`
`
`
`
`
`
`5
`
`

`
`‘emy
`
`717
`Opioid Analgesics
`
`
`)n
`
`9
`
`2. Opioid Agonists Conveniionolly
`Used for Moderate Pain
`
`Codeine, dihydrocodeine, hydrocodone, oxy-
`codone and dextropropoxyphene are typically pre-
`scribed in low dose formulations in combination
`
`with either aspirin or paracetamol (acetamino-
`phen). All of these drugs have a short half-life and
`a duration of action of typically 2 to 4 hours. Using
`these formulations, the dose of these combination
`
`products can be increased until the maximum dose
`of the nonopioid co-analgesic is attained (e. g. para-
`cetamol 4000 to 6000 mg/day; beyond this dose,
`the opioid contained in the combination product
`could be increased as a single agent, or the patient
`could be switched to an alternative pure agonist
`opioid.
`Controlled release (CR) formulations of co-
`
`deine,[9] dihydrocodeinellol and oxycodonemtlzl
`are currently under development. When available,
`these formulations will substantially improve the
`convenience of therapy with these drugs for pa-
`tients with chronic pain. An alternative approach
`for patients with moderate pain incorporates the
`use of low doses of a pure agonist such as morphine
`or oxycodone.
`
`Table III. Classification of opioid analgesics
`Agonists
`Agonist-antagonists
`Conventionally used for
`Pentazocine,
`moderate pain: codeine,
`butorphanol,
`oxycodone,
`nalbuphine,
`dihydrocodeine,
`meptazinol
`dextropropoxyphene,
`tramadol
`
`Partial agonists
`Buprenorphine
`
`Conventionally used for
`strong pain, short
`half-/ife: morphine,
`oxycodone,
`oxymorphone, pethidine
`(meperidine),
`phenazocine,
`diamorphine (heroin),
`fentanyl
`Conventionally used for
`strong pain, long ha/f-life:
`methadone, levorphanol
`
`2.l Codeine
`
`Codeine is the most commonly used opioid
`analgesic for the management of mild to moderate
`pain. It is most commonly used in combination
`with aspirin or paracetamol. Although some vari-
`ability is observed, its plasma half—life and dura-
`tion of action are usually in the range of 2 to 4
`hours.
`
`2.2 Dihydrocodeine
`
`Dihydrocodeine is an equianalgesic codeine an-
`alogue. In the US it is only available in combina-
`tion with paracetamol or aspirin. A single agent CR
`formulation, useful for chronic pain of moderate
`intensity, is available in some countries.“°~13l
`
`2.3 Hydrocodone
`
`Hydrocodone has an oral analgesic potency that
`is approximately half that of oral morphine. It is
`available in the US in a combination tablet that
`
`incorporates hydrocodone 10mg with paracetamol
`l000mg.“4]
`
`2.4 Oxycodone
`
`Oral oxycodone has a high bioavailability
`(60%) and an analgesic potency that is comparable
`to that of morphine.“5l There are limited data to
`suggest that oxycodone is associated with a lower
`likelihood of hallucinations than morphine.“5]
`
`2.5 Dextropropoxyphene
`
`Dextropropoxyphene is a congener of metha-
`done. Its major metabolite, norpropoxyphene, has
`a long half-life and is associated with excitatory
`effects including tremulousness and seizures.“6]
`These effects are dose-related and are not a clinical
`
`problem at the doses of dextropropoxyphene typi-
`cally administered for moderate pain in the non-
`tolerant patient (50 to 100mg every 4 hours)§“7l
`
`2.6 Tramadol
`
`Tramadol is a new centrally acting analgesic
`which possesses opioid agonist properties and
`
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`Cherny
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`Drugs 19% May: 51 (5)
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`eventuates in a long half-life in cerebrospinal fluid
`(CSF) of 90 to 120 minutes and extensive rostral
`redistribution.[37]
`
`Morphine undergoes hepatic glucuronidation at
`the 3 and 6 positions, and the metabolites are_ex—
`creted by the kidneys. Morphine—3-glucuronide
`(M3G), the major metabolite,[23] is not an analge-
`sic. There is some evidence that it is an opioid
`antagonist[”} and that M3G concentrations may be
`associated with adverse effects[3°] including the
`uncommon phenomenon of hyperalgesia (so-
`called ‘paradoxical pain’) after morphine adminis-
`tration.[3‘-33] Morphine-6-glucuronide (M6G) binds
`to opioid receptors[33I and produces potent opioid
`effects in animals[33’35] and humans.[33~36'39] M6G
`
`excretion by the kidney is directly related to calcu-
`lated creatinine clearance.[33] In patients with im-
`paired renal function, M6G may accumulate in
`blood and CSF,[4°] and high concentrations of M6G
`have been associated with toxicity.[36"“v“‘3] These
`data suggest the need for caution when administer-
`ing morphine to patients with renal impairment.
`Single dose studies of morphine in postopera-
`tive cancer patients demonstrated an intramuscular
`to oral (IM : PO) potency ratio of l : 6 (table II).[43l
`However, both bioavailability data[35-4446] and sur-
`veys of patients receiving the drug long term sug-
`gest that a ratio of l
`: 3 or 1 : 2 is more appropriate
`for routine clinical use.[47*48] The usual practice
`when converting from oral morphine to subcutane-
`ous morphine is to divide the oral dose by 2 or 3.
`The development of CR morphine preparations
`has had a major impact on clinical practice. These
`preparations, which can be administered as an 8-
`or 12-hour regimen, provide a much more conve-
`nient means of administering oral morphine.[49]
`They are widely available with a range of tablet
`strengths (l0, l5, 30, 60, 100 and 200mg, depend-
`ing on the country) allowing considerable flexibil-
`ity in its use. In addition to the tablets which are
`
`routinely available, CR suspension[5°] and suppos-
`itories[5” are under development.
`In contrast to morphine elixir or immediate re-
`lease tablets with which peak plasma concentra-
`tions (Cmax) are achieved within the first hour fol-
`
`
`
`,.-.__..._._,._,....
`
`
`
`
`
`
`which also activates monoaminergic spinal inhibi-
`tion of pain.“31 It has modest affinity to opioid u
`receptors and has weak affinity to 5 and K recep-
`tors. Its analgesic effect is partially reversed by nal-
`oxone.“3] Unlike other opioids, it also inhibits the
`uptake of noradrenaline (norepinephrine) and sero-
`tonin (5—HT; 5-hydroxytryptamine).[13]
`Tramadol may be administered orally, rectally,
`intravenously, subcutaneously,
`intramuscularly
`and via spinal routes. Data from a double-blind,
`crossover study suggest that oral tramadol 120mg
`is equipotent to oral morphine 3Omg.“9] Intra-
`venous tramadol is approximately one-tenth as po-
`tent as morphine.[3O] Tramadol is generally well tol-
`erated, with dizziness, nausea, sedation, dry mouth
`and sweating being the principal adverse effects.
`Respiratory depression is uncommon.[3°~2”
`
`3. Opioid Agonists Conveniionally Used
`for Severe Pain
`
`3.i Short Hc1lf—Life Drugs
`
`3.1.1 Morphine
`
`Morphine, the main naturally occurring opioid
`derived from the Papaver somnzferum poppy plant,
`is available for therapeutic use as the sulphate,
`hydrochloride and tartrate. Morphine is available
`in 3 oral formulations, an elixir, a conventional re-
`lease tablet, and a CR tablet (of which there are
`now several preparations using different CR mech-
`anisms). In healthy volunteers and cancer patients
`the average bioavailability for oral morphine is 20
`to 30%.m‘25]
`
`The sulphate and hydrochloride salts of mor-
`phine have limited solubility; formulations of up to
`20 mg/ml are routinely available, and they can be
`constituted from lyophilised powder in concentra-
`tions of up to 50 mg/ml. Morphine tartrate is sub-
`stantially more soluble and, in some countries, is
`formulated in a concentration of 80 mg/ml.[26]
`In patients with normal renal function the
`plasma half-life of morphine is 2 to 3 hours. Mor-
`phine is relatively hydrophilic and, when adminis-
`tered epidurally or intrathecally, is not rapidly ab-
`
`sorbed into the systemic circulation. This property
`
`
`7
`
`

`
`
`
`Opioid Analgesics
`
`
`719
`
`lowed by a rapid decline with an elimination half-
`life of 2 to 4 hours, CR morphine typically achieves
`a Cmax 3 to 6 hours after administration, the peak
`is attenuated (compared with a conventional re-
`lease formulation), and plasma concentrations are
`sustained over a 12-hour period.
`Initial dose titration using CR morphine is dif-
`ficult because of the delay in achieving Cmax, the
`attenuation of Cmax, and the long duration of ac-
`tion. Dose finding in these situations is performed
`more efficiently with a short—acting morphine
`preparation. Once the effective dose is identified
`using a conventional release formulation, this may
`be changed to a CR preparation using a milligram
`to milligram conversion. For the same reasons, CR
`morphine is not appropriate for the treatment of
`acute or ‘breakthrough’ pain. A conventional re-
`lease morphine preparation should be provided to
`patients stabilised on CR morphine to be used ‘as
`required’ for breakthrough pain.
`
`3. 7.2 Diamorphine (Heroin)
`Diamorphine is available for legal medicinal
`use only in the UK and Canada. Diamorphine is a
`prodrug that must be biotransformed to 6-acetyl-
`morphine and morphine to produce its analgesic
`effect.[53l Oral diamorphine is an inefficient way of
`delivering morphine to the systemic circulation;
`after the oral administration of diamorphine, only
`morphine can be measured in the patient’s blood.
`Diamorphine is approximately twice as potent
`as morphine by subcutaneous or intramuscular
`injection[53l because of its greater solubility and
`lipophilicity. The high solubility of diamorphine
`(shared also with hydromorphone and morphine
`tartrate) is of particular advantage for patients who
`require large doses of subcutaneous opioids.
`
`3.1.3 Pethidine (Meperidine)
`Pethidine is a synthetic opioid with agonist ef-
`fects similar to those of morphine but a profile of
`potential adverse effects that limits its utility in
`patients who require repeated administration. In-
`tramuscular pethidine 75mg is equivalent to intra-
`muscular morphine 10mg. Pethidine has an oral
`bioavailability of 40 to 60% and its IM : PO rela-
`tive potency ratio is l : 4 (table II). Its duration of
`
`action after parenteral administration is 2 to 3
`hours.
`
`Pethidine is N-demethylated to norpethidine,
`which is an active metabolite that is twice as potent
`
`a convulsant and one-half as potent an analgesic as
`its parent compound. Accumulation of norpethid-
`ine after repetitive administration of pethidine can
`result in CNS excitability characterised by subtle
`mood effects, tremors, multifocal myoclonus and
`occasionally seizures.l54'56] Naloxone does not re-
`verse pethidine-induced seizures and it is possible
`that its administration to patients receiving pethid-
`ine in the long term could precipitate seizures by
`blocking the depressant action of pethidine and al-
`lowing the convulsant activity of norpethidine to
`become manifest.l57l If naloxone is necessary in
`this situation, it should be diluted and slowly ti-
`trated while appropriate seizure precautions are
`taken.
`
`Although accumulation of norpethidine is most
`likely to affect patients with overt renal disease,
`toxicity is sometimes observed in patients with
`normal renal function.[54~56~53l Given the availabil-
`ity of alternative drugs that lack these toxicities,
`its use in acute pain management is not recom-
`1nended[59l and it is relatively contraindicated for
`the management of chronic cancer pain.[59l
`
`3. 1.4 Hydromorphone
`Hydromorphone is a versatile, short half—life
`opioid that can be administered by the oral, rectal,
`parenteral and intraspinal routes.l6°] It is a particu-
`larly useful drug for subcutaneous infusions be-
`cause of its solubility (and the commercial avail-
`ability of a high concentration preparation 10
`mg/ml product) and proven equivalence to intra-
`venous administrationié” For patients who require
`very high opioid doses via the subcutaneous route,
`hydromorphone can be constituted in concentra-
`tions of up to 50 mg/ml from lyophilised powder.
`It is also available in 2, 4 and 8mg tablets and 3mg
`suppositories, all of which usually require 3- to
`4—hourly administration. A CR formulation of oral
`hydromorphone is under development and should
`soon become available.[62l
`
`© Adis International Limited. All rights reserved.
`
`Drugs 1996 May; 51 (5)
`
`8
`
`

`
`
`
`
`
`Oxycodone is a synthetic morphine congener
`which has a high oral bioavailability (60 to 90%)
`and an analgesic potency that is comparable to that
`of morphine.“5v45v64l In formulations combined
`with aspirin or paracetamol it is commonly used for
`moderate pain. As a single agent tablet or syrup it
`can be used to manage severe pain effectively.[65]
`Using currently available oral formulations this
`drug usually requires 3- to 4—hourly administration.
`In some countries, oxycodone pectinate is avail-
`able as a 30mg rectal suppository which has a de-
`layed absorption and prolonged duration of ef-
`fect.[66] There are limited data to suggest that
`oxycodone is associated with a lower likelihood of
`hallucinations than morphine.“5l
`
`© Adis International Limited. All rights reserved.
`
`Drugs 19% May: 51 (5)
`
`
`Hydromorphone is hydrophilic and, when ad-
`ministered via the epidural route, its pharmaco-
`kinetics, including its long half—life and extensive
`rostral distribution in CSF, are similar to those of
`morphine.[°3l
`
`3.1.5 oxycodone
`
`3. 1.6 Oxymorphone
`
`Oxymorphone is a potent, short half-life conge-
`ner of morphine that is available in the US as in-
`jectable and rectal formulations. Oxymorphone is
`less likely to produce histamine release than mor-
`phine, and may have particular utility for patients
`who develop itch in response to other opioids.l67~63]
`
`3. 1.7 Fentanyl
`
`Fentanyl is a semisynthetic opioid characterised
`by high potency and lipophilicity, and a short half-
`life after bolus administration. Like all other highly
`lipid—soluble drugs, its elimination half-life is in-
`fluenced by the duration of prior administration
`which determines the extent of fat sequestration; in
`steady—state the elimination half-life is usually 7 to
`12 hours.
`
`The development of a transdermal administra-
`tion system has broadened its clinical utility for the
`management of cancer pain.[69‘7” Arecently devel-
`oped oral transmucosal formulation may be useful
`in the management of breakthrough pain in the can-
`cer populationml Fentanyl is also used parenter-
`
`ally as a premedication for painful procedures[591
`and in continual infusion.l73]
`
`A transdermal formulation of fentanyl that de-
`livers 25, 50, 75 or 100 ug/h is commercially avail-
`able. The transdermal system consists of a drug
`reservoir that is separated from the skin by a co-
`polymer membrane that controls the rate of drug
`delivery to the skin surface. Drug is released at a
`nearly constant rate along a concentration gradient
`from the patch to skin. After application of the
`transdermal system, serum fentanyl concentrations
`increase gradually, usually levelling off at 12 to 24
`hours, then remaining stable for a time before de-
`clining slowly. When the patch is removed, serum
`
`concentrations fall 50% in approximately 17 hours
`(range 13 to 22 hours).[59] The slow onset of effect
`after application and an equally slow decline in ef-
`fect after removal are consistent with the develop-
`ment of a subcutaneous depot of drug that main-
`tains the plasma concentration.
`
`There is significant interindividual variability in
`fentanyl bioavailability by this route, and dose ti-
`tration is necessary.l7°~7‘” The dosage interval for
`each system is usually 72 hours, but interindividual
`
`pharmacokinetic variability is large[7°~74v75] and
`some patients require a dosage interval of 48 hours.
`Empirical observations suggest that a 100 ug/h fen-
`tanyl patch is approximately equianalgesic to 2 to
`4 mg/h of intravenous morphine.
`Empirically, the indications for the transdermal
`
`route include intolerance of oral medication, poor
`compliance with oral medication, and occasion-
`
`ally, the desire to provide a trial of fentanyl to pa-
`tients who have reacted unfavourably to other op-
`ioids. Limitations of the transdermal delivery
`system include its cost, the requirement for an al-
`
`ternative short-acting opioid for breakthrough pain
`and poor adhesion to skin in some patients.
`
`3. 1.8 Alfentanil and sufentanil
`
`Alfentanil and sufentanil are fentanyl analogues
`characterised by a short latency, duration of action
`and elimination half-life. They are most commonly
`used as an intraoperative anaesthetics.[76]
`
`9
`
`

`
`Opioid Analgesics
`
`
`721
`
`3. 1.9 Phenazocine
`
`Phenazocine is a synthetic opioid structurally
`related to morphine. One 5mg tablet is equivalent
`to oral morphine 25mg.[77] Phenazocine may be
`given sublingually,[78l though ad