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Ovid: Oxford Handbook of Palliative Care

Editors: Watson, Max S.; Lucas, Caroline F.; Hoy, Andrew M.; Back, Ian N. Title: Oxford Handbook of Palliative Care, 1st Edition Copyright ©2005 Oxford University Press > Table of Contents > Symptom Management > Chapter 6a – The management of pain > Opioid analgesic therapy Opioid analgesic therapy Paracetamol and weak opioids Codeine Five to ten per cent of caucasians are CYP2D6 poor-metabolizers, an hepatic enzyme necessary to convert codeine to morphine. These patients will not obtain equivalent analgesia using codeine-containing analgesics. This bioactivation is markedly inhibited by antipsychotics (chlorpromazine, haloperidol, levomepromazine, and thioridazine), metoclopramide, and tricyclic antidepressants (amitriptyline etc.). If hepatic metabolism is decreased in patients taking these drugs, or with liver disease, the analgesic action of codeine may also be compromised. Co-proxamol Systematic reviews suggest that co-proxamol (dextropropoxyphene and paracetamol) is no more effective as an analgesic than paracetamol alone. Dextropropoxyphene has a longer elimination half-life than paracetamol and will therefore accumulate to higher blood levels during repeated dosing. Compound analgesics containing sub-therapeutic doses of opioids should not be used for pain control in cancer patients.1 The UK Committee of Safety of Medicines decided in January 2005 to withdraw co-proxamol use in the UK over a 12 month period because of its efficacy and safety profile. Morphine We are all strong enough to bear the misfortunes of others. Duc de la Rochefoucauld 1613–80: Maximes (1678) Morphine is the strong opioid of first choice for moderate to severe cancer pain. Alternative opioids may be as effective, and are appropriate for certain patients. Starting a patient on morphine

  • Start with immediate release (i/r) morphine liquid or tablets
    • Adult, not pain controlled on regular weak opioids: 10mg 4-h morphine
    • Elderly, cachectic, or not taking regular weak opioids: 5mg 4-h morphine
    • Very elderly and frail: 2.5mg 4-h morphine
  • Although 4-h morphine gives greatest flexibility for initial dose titration, patients with less severe pain, difficulties with compliance and especially outpatients, can be started on 12-h modified release (m/r) morphine:
    • Adult, not pain controlled on regular weak opioids: 15–30mg 12-h morphine m/r
    • Very elderly and frail: 10mg 12-h morphine m/r
  • Always prescribe a laxative concurrently
  • Consider prescribing a regular antiemetic for those with a history of nausea/vomiting, e.g. haloperidol 1.5mg nocte: this can usually be stopped after a week. If not prescribed prophylactically, warn the patient to report any nausea so that an antiemetic can be prescribed as soon as possible
  • Explain to patients that any drowsiness will usually wear off after a few days
  • P.185

  • Advise patients not to drive, for at least one week after starting morphine, or after any increase in dose. Patients should continue to avoid driving even after this time of drowsiness persists

Footnotes 1 Scottish Intercollegiate Guidelines Network (2000). Control of pain in patients with cancer. Edinburgh: SIGN. Titrating dose of morphine

  • Increase the dose as needed by increments of 25–50 per cent rather than by a fixed amount. The increment percentage tends to decrease a little as the dose increases e.g. 5–10–15–20–30–40–60–80–100–130–160–200mg. There is no pre-set maximum dose of opioids as long as increasing the dose gives further analgesia. Very few patients will require more than 600mg daily
  • When pain is reasonably well controlled consider converting to modified release morphine 12-h for convenience of b.d. administration

Morphine preparations Morphine (immediate release, 4-h)

  • Mixture 10mg/5ml (Oramorph/Sevredol)
  • Mixture 20mg/ml (Oramorph concentrated/Sevredol concentrated)
  • Tabs. 10, 20, 50mg—scored Tabs. (Sevredol)

Morphine Unit Dose Vials

  • Vials. 10, 30, 100mg all in individual 5ml vials (Oramorph Unit Dose Vials)

Morphine preparations, (modified release, 12-h) MST and Zomorph can be used interchangeably. MST Continus (Morphine m/r)

  • Tabs. m/r 5, 10, 15, 30, 60, 100, 200mg
  • Susp. 20, 30, 60, 100, 200mg

Sachets to prepare Susp. Zomorph caps. (Morphine m/r)

  • caps. m/r 10, 30, 60, 100, 200mg Can be broken and administered via a NG/PEG tube, or sprinkled on food. Bioequivalent to MST

Morphine preparations—modified release (24-h) MXL (Morphine m/r)

  • caps. m/r 30, 60, 90, 120, 150, 200mg

Morcap m/r (Morphine m/r)

  • caps. m/r 20, 50, 100mg

May not be bioequivalent to MST Morphine preparations—rectal (4-h) Morphine Supps.

  • Supps. 10mg 15mg 20mg, 30mg
  • Equianalgesic dose by oral and rectal routes

Converting to 12-h morphine Divide daily morphine intake by half to give 12-h dose (e.g. morphine 10mg 4-h → 30mg morphine m/r 12-h). Ensure the patient has access to immediate release morphine for breakthrough pain. A dose of morphine of 50–100% of the 4-h dose equivalent may be taken for breakthrough pain. P.186
Diamorphine Diamorphine is more soluble in water than morphine, and is commonly used as the injectable strong opioid in a syringe driver for subcutaneous infusion. To convert from oral morphine to SC diamorphine, divide the total dose of oral morphine by 3 e.g. 10mg 4-h morphine [approximate, equals]60mg oral morphine in 24h [approximate, equals]20mg diamorphine by CSCI over 24h e.g. morphine 3mg p.o. [approximate, equals]Diamorphine 1mg by SC injection Increments in dose should be between 25–50 per cent as for oral morphine. Additional SC doses for ‘breakthrough’ pain should be 50–100 per cent of the equivalent 4-h dose. If vomiting or no longer able to swallow medication, convert to a subcutaneous infusion of diamorphine via a syringe driver by dividing the 24-h total dose of oral morphine by three. Breakthrough doses Use 50–100 per cent of the equivalent 4-h dose currently being used e.g.

  • for a patient on morphine m/r 270mg 12-h: [approximate, equals]540mg oral morphine in 24h [approximate, equals]90mg morphine p.o. 4-h i.e. use breakthrough dose 45–90mg morphine p.o. 4-h p.r.n.
  • for a patient on 180mg diamorphine SC in 24h [approximate, equals]30mg diamorphine SC 4-h i.e. use breakthrough dose of 15–30mg diamorphine SC 4-h

Intravenous use for pain emergencies Various different protocols have been described for intravenous titration of opioids for severe pain ‘emergencies’.

  • monitor respiratory rate and conscious level regularly
  • draw up diamorphine diluted to 10ml with water
    • If opioid naive dilute 5mg of diamorphine in 10ml of water
    • If on regular opioid use equivalent 4-h dose based on previous opioid use in last 24h (see ‘Breakthrough doses’ above) diluted in 10ml water
  • give appropriate diamorphine dilution i/v at 1ml/minute (total over 10 minutes)
  • stop if pain <5/10 or toxicity develops
  • repeat the above after a further 10–20 minutes if required
  • calculate the total dose of diamorphine administered and multiply by 6
  • start maintenance infusion with CSCI, or regular oral morphine equivalent dose over 24h

NB It is unusual to give diamorphine intravenously in a hospice setting. Subcutaneous administration is most commonly used (takes 10 to 20 minutes to work) unless the pain is very severe and immediate relief is needed. Diamorphine preparations Inj. 5mg, 10mg, 30mg, 100mg, 500mg P.187
Alternative strong opioids A number of alternative strong opioid analgesics are available which have their place in palliative care:

Table 6a.2a Alternative strong opioids
Morphine and similar drugs Morphine
Fentanyl and similar drugs Fentanyl
Methadone Methadone
Intermediate weak–strong opioid Tramadol
Other opioids occasionally used Buprenorphine
Not recommended Pethidine

Differences between these drugs are not fully understood, but include patient factors and drug factors. In clinical practice they may be divided into: Morphine-like opioids Oxycodone and hydromorphone, like morphine and diamorphine, are available in a wide range of doses in immediate (4-h) and modified release oral preparations. They can be used by CSCI. Although there may be small intrinsic differences between the side-effect profiles of these drugs (e.g. oxycodone and hydromorphone may cause less toxicity than morphine in patients with renal failure, but neuroexcitatory side-effects are still reported), inter-individual variability seems to be a greater factor in determining the clinical picture. Substituting one opioid for another may reduce side-effects in up to 75 per cent of selected individuals. Fentanyl and its analogues Fentanyl and its analogues (alfentanil, sufentanil and remifentanil) are selective µ receptor agonists, unlike morphine. They may cause less sedation, cognitive impairment and constipation than morphine-like drugs in some patients. They are largely inactive orally because of high first-pass hepatic metabolism, but can be used by transdermal patch, oral lozenge (buccal absorption) or CSCI. Fentanyl does not appear to accumulate and cause toxicity in renal failure. Methadone Methadone is an agonist at the µ- and δ-opioid receptors, and also an NMDA receptor antagonist and monoamine reuptake inhibitor. These actions make it a useful treatment for neuropathic and other pain states not fully responsive to morphine. However, it has a long and variable elimination half-life, making it difficult to use safely, and should be reserved for neuropathic, ischaemic or inflammatory pain, or use as a third- or fourth-line opioid. P.188
Tramadol Tramadol may be classed somewhere between the weak and strong opioids. It has additional pharmacological actions to its opioid effects. It is not classed as a ‘controlled drug’ which has some practical prescribing advantages. Tramadol is a synthetic analogue of codeine that binds to µ-opioid receptors and also inhibits norepinephrine and serotonin reuptake. It is rapidly and extensively absorbed after oral doses and is metabolized in the liver. Analgesia begins within one hour and starts to peak in two h. In studies comparing equianalgesic doses of oral tramadol (up to 300 mg/day) and oral morphine for moderate cancer pain, constipation, nausea, neuropsychological symptoms, and pruritus were reported more frequently with morphine. Slow release formulations have also been shown to provide effective relief of moderate cancer pain. Tramadol preparations

  • caps. 50mg; Sachets effervescent powder 50mg; Sol. Tabs. 50mg
  • Tabs. m/r (12-h) 75mg, 100mg, 150mg, 200mg
  • caps. m/r (12-h) 50mg, 100mg, 150mg, 200mg
  • Tabs. m/r (24-h) 150mg, 200mg, 300mg, 400mg

Starting dose: 50mg q.d.s. p.o. or 100mg b.d. p.o. (12-h m/r) Inj. 100mg/2ml Buprenorphine For many years palliative care physicians have been concerned about the use of buprenorphine because of potential problems encountered when patients taking regular morphine were given buprenorphine with consequent exacerbation of pain. Although buprenorphine is a very potent analgesic that strongly binds to opioid receptors displacing other opioids, it is a less effective analgesic. The introduction of buprenorphine patches has caused such opinions to be revisited. Other opioids can be used in conjunction with buprenorphine patches if pain breaks through. Side-effects of buprenorphine are similar to those of other strong opioids. Care needs to be taken with patients who are sweating heavily to ensure that the patch is sticking well to the skin.

  • For opioid naïve patients the starting dose recommended by the manufacturers is 35mcg/h
  • No more than two patches should ever be applied at the one time
  • The maximum dose is 140 mcg/h
  • The patch should be changed every three days

Buprenorphine preparations

  • Patch strength 35, 52.5, 70 mcg/h

Applied every three days. Packs of 5 patches:

  • Tabs. (sublingual) 200mcg

Other opioid analgesics Pethidine has a short duration of action, and, when given regularly, active metabolites accumulate and can cause convulsions. It causes more dysphoria than morphine and is best avoided in palliative care. P.189
Indications for starting with an opioid other than morphine:

  • Patient choice
  • Subacute/partial intestinal obstruction. A less constipating opioid such as fentanyl may be appropriate
  • Patient reluctant to take ‘morphine’ despite appropriate counselling
  • Patient reluctant to take oral medication regularly
  • Renal failure

Indications for changing to alternative opioids This practice is known as opioid rotation or opioid substitution.

  • Patient choice
  • Unacceptable side-effects with current opioid
  • Renal failure
  • Route of administration needs to be changed from oral as cannot swallow

Choice of alternative opioid Rationale

  • Hydromorphone, oxycodone and fentanyl are useful alternatives to morphine and diamorphine
  • Methadone is difficult to use safely, and should be reserved for neuropathic, ischaemic or inflammatory pain, or used as third- or fourth-line opioid under specialist supervision
  • Few strong opioids other than morphine have the range of doses and preparations needed to be suitable for routine use in cancer pain
  • There is little to choose between oxycodone and hydromorphone, but oxycodone is chosen in preference because:
    • a liquid immediate release preparation is available
    • an injectable form is readily available in the UK
    • doses are simpler to calculate
    • there is less variation in the reported equianalgesic ratios
    • the manufacturer’s recommended conversion of 7.5:1 for morphine to hydromorphone is higher than the more commonly used ratio of 5:1. This makes the tablet doses of 1.3mg even more complicated
  • Fentanyl may cause less side-effects in some individuals (sedation, cognitive impairment, constipation, myoclonus and pruritus)
  • Transdermal patch or CSCI are the only methods of administering fentanyl regularly for chronic pain as fentanyl has a short half life

Dose titration for unstable pain should not be attempted using a fentanyl patch P.190
Oxycodone Oxycodone is a strong opioid analgesic similar to morphine. It is available in 4-h immediate- release, and 12-h release preparations. It is a useful, though more expensive, alternative opioid in selected patients who develop side effects with morphine. The receptor affinity of oxycodone is not fully clear. It is partially metabolized to potent oxymorphone. Oxycodone is approximately 1.5–2 times as potent as morphine orally. Side-effects The side-effects are similar to morphine though vomiting, itch, and drowsiness may be less common in some individuals.2 Indications Alternative opioid when morphine causes unacceptable side-effects. Using oxycodone Oxycodone should be used in the same way as morphine (remember to prescribe a laxative). Comparison with morphine In comparative studies with morphine, there are inconsistent reports of side-effect profiles. More vomiting has been reported with morphine, whereas constipation was more common with oxycodone. Other studies have shown no difference. When selectively substituting morphine for oxycodone in patients with side-effects, improvements in almost all side-effects have been reported: less nausea, hallucinations, drowsiness, sweating and pruritus, but especially confusion/delirium. These reports do not necessarily reflect an overall difference between the drugs, but may reflect inter-individual variation. Hepatic metabolism Oxymorphone, a potent analgesic metabolite of oxycodone, is formed by the hepatic enzyme CYP2D6, which is under polymorphic genetic control. The rôle of oxymorphone in the analgesic effect of oxycodone is not yet clear. Oxycodone conversion to oxymorphone may be important for analgesic effect in some patients, and genetically ‘poor-metabolizers’ may not obtain the expected analgesia from oxycodone. Synergy between opioids In animal models, a combination of sub-analgesic doses of oxycodone and morphine showed synergy producing analgesia. Oxycodone

  • caps. 5mg, 10mg, 20mg (OxyNorm)
  • caps. m/r (12-h) 10mg, 20mg, 40mg, 80mg (OxyContin)
  • Liquid 5mg/5ml, 10mg/1ml

Manufacturers recommended conversion from oral morphine to oxycodone: divide morphine dose by 2.

  • Injection: 10mg/ml 1ml and 2ml Amp

Manufacturers recommended conversion from oral oxycodone to subcutaneous oxycodone: divide dose by 2. Footnotes 2 Heiskanen T, and Kalso E. (1997) Controlled-release oxycodone and morphine in cancer related pain. Pain, 73: 37–45. P.191
Hydromorphone Hydromorphone is a strong opioid analgesic very similar to morphine, although it is a more selective µ-receptor agonist. It is used widely in North America as an alternative to diamorphine, which is not available. It is available in 4-h immediate release, and 12-h modified release preparations, but the injection is not routinely available in the UK. It is a useful alternative opioid in selected patients who develop side effects with morphine. Hydromorphone has been used successfully and without toxicity in renal failure, but it has also been reported to cause neuro-excitatory effects in some patients (

Figure. No caption available.

see renal failure later). Indications

  • Alternative opioid if morphine causes unacceptable side-effects, especially—
    • Opioid-induced pruritus

Using hydromorphone

  • Hydromorphone should be used in the same way as morphine (remember to prescribe a laxative)
  • The capsules can be broken open and sprinkled on soft cold foods

Cough and dyspnoea Information about the efficacy of alternative opioids for symptoms other than pain is limited. Hydromorphone may help cough and dyspnoea in lower doses than those used for analgesia. Conversion ratios with other opioids Conversion ratios between hydromorphone and other strong opioid analgesics seem more variable and uncertain than for other opioids, perhaps representing greater variability in metabolism and bioavailability (10–65 per cent) between individuals.

  • When converting from oral morphine to oral hydromorphone, the manufacturers recommend a ratio of 7.5:1 (i.e. morphine 10mg ≈ hydromorphone 1.3mg)
  • It is suggested that the lowest potency ratio is used for any conversion, with the expectation of titrating up the dose rapidly if needed

Side-effects Hydromorphone and morphine generally have the same side-effects. Pruritus, nausea and vomiting, sedation and cognitive impairment, which may be less common with hydromorphone. There may also be individual variation in side-effect profile between patients. Drug preparations-Hydromorphone

  • caps. 1.3mg, 2.6mg (Palladone)
  • caps. m/r (12-h) 2mg, 4mg, 8mg, 16mg, 24mg (Palladone SR)

Manufacturers recommended conversion from oral morphine: divide morphine dose by 7.5

  • Inj. 10mg/1ml 20mg/1ml 50mg/1ml Injections available in UK as a special order from Martindale. See BNF for contact details.

Fentanyl Fentanyl is a selective µ-receptor agonist (morphine acts on µ and κ receptors). It has been promoted as causing less constipation, sedation, and cognitive impairment than oral opioids. Fentanyl may be associated with a slightly higher incidence of nausea than morphine. As it has inactive metabolites and is metabolized mainly in the liver, it is less likely to cause adverse effects in uraemic patients. As it is more selective than morphine, fentanyl will not relieve pain that is resistant to morphine, but may help patients with morphine-responsive pain who develop intolerable side-effects to morphine. Fentanyl is available as a transdermal patch, oral lozenge (buccal absorption), or can be given CSCI. CSCI is better than a patch for establishing effective blood levels rapidly, and should be used when speed is important, or when more flexibility is desired. Converting a patient from morphine to fentanyl can lead to a modified withdrawal syndrome of shivering, diarrhoea, bowel cramps, sweating and restlessness, even though pain relief is maintained. These symptoms can be relieved with morphine given p.r.n. for a few days. Fentanyl toxicity may be clinically more subtle than morphine toxicity and may present as vagueness, drowsiness or ‘not feeling well’. Indications Alternative opioid when morphine causes unacceptable side-effects.

  • Starting a strong opioid in a patient with:
    • a history of subacute bowel obstruction (less constipating than morphine)
    • renal failure (which can lead to myoclonus or confusion with morphine due to metabolite accumulation)
    • biliary colic/obstructed bile duct (see additional notes below)
  • Patient acceptability/compliance

Transdermal fentanyl patch—only when pain is stable

  • Start with 25mcg/h, or convert dose from morphine
  • It takes 12–24h to achieve therapeutic blood levels, and approximately 72h to reach steady-state:
    • CSCI of fentanyl or alfentanil will achieve more rapid blood levels
  • If converting from morphine, give last dose of 12-h modified release morphine when applying patch except when accumulation of opioids in renal failure has occurred
  • If converting from morphine, remember the possibility of withdrawal symptoms and use immediate release morphine p.r.n. until symptoms settle
  • Up to 25 per cent of patients need a patch change every 48h
  • Use either oral morphine or oral transmucosal fentanyl for breakthrough pain
  • Fever may increase drug absorption due to vasodilation
  • Sweating may decrease drug absorption because it prevents the patch from sticking to the skin
  • After removal of the patch, blood levels decrease by only 50 per cent in 18h
  • P.193

  • Mild to moderate skin erythema or pruritus in the location of the patch have been reported in <5 per cent of patients

Fentanyl patches Absorption rate from a fentanyl transdermal patch is roughly proportional to the surface area in contact with the skin. Various techniques have been used to allow only half of the area to contact with the skin—to approximate to a 12.5mcg/hour dose delivery. Tegaderm or Opsite dressings, with the fentanyl patch placed half on skin/half over the dressing, have been used, but note that these dressings are semipermeable. Others have folded the patch in half and covered with adhesive tape. Although the delivered analgesic effect may theoretically be less, the side-effect profile does not alter. Neither method is recommended by the manufacturers. Some patients develop itching and irritation at the site of transdermal patches—reports suggest that spraying the skin with aerosol corticosteroid spray may be effective (use beclometasone dipropionate aerosol inhaler 50mcg/dose). Subcutaneous fentanyl

  • Calculate dose as equivalent to transdermal patch e.g. 25mcg/h = 600mcg/24h; for convenience (and considering the widely variable absorption from a patch) use 500mcg/24h CSCI as equivalent to a 25mcg/h patch
  • Large volumes are needed for high doses: consider substituting alfentanil (see next section)
  • Compatible with most commonly used drugs in palliative care

Oral transmucosal fentanyl citrate (OTFC) Fentanyl lozenges (on a stick) are rapidly absorbed through the buccal mucosa, leading to onset of pain relief within 5–10 minutes. The maximum effect is reached within 20–40 minutes with a duration of action of 1–3h. Bioavailability is about 50 per cent. One comparative study suggests they may give better results than immediate release oral morphine. Indication Breakthrough pain in patients on regular strong opioid therapy. Use The optimal dose is determined by titration, and cannot be predicted by a patient’s regular dose of opioid. Approximately 25 per cent of patients fail to obtain relief even at the highest dose, or have unacceptable adverse effects.

  • Lozenge should be placed in the mouth and sucked, constantly moving it from one cheek to the other
  • Should not be chewed
  • Water can be used to moisten the mouth beforehand
  • The lozenge should be consumed within 15min
  • Partially consumed lozenges should be dissolved under hot running water, and the handle disposed out of reach of children

Dose titration

  • Initial dose is 200mcg, regardless of dose of regular opioid. This dose is probably approx. equivalent to morphine 2mg i/v
  • A second lozenge of the same strength can be used if pain is not relieved after 15 minutes
  • No more than two lozenges should be used to treat any individual pain episode
  • Continue with this dose for a further 2–3 episodes of breakthrough pain, allowing the second lozenge when necessary
  • If pain still not controlled, increase to the next higher dose lozenge
  • Continue to titrate in this manner until dose is found that provides adequate analgesia with minimum adverse effects
  • No more than four doses per day should be used (regular strong opioid dose should be increased)

Inflammatory and neuropathic pain A few observations suggest that fentanyl (and similar analogues) may be less effective than morphine for inflammatory or neuropathic pain. This may be explained by the additional effects of morphine (e.g. at kappa or delta receptors). Dose equivalence Manufacturer’s recommended dose conversion from oral morphine to transdermal fentanyl patch is based on a ratio of 150:1 (i.e. 15 mg morphine p.o 4-h [approximate, equals] 25mcg/h patch). Manufacturers information sheets should be consulted. Bile duct obstruction Many opioid µ-receptor agonists, including morphine and diamorphine, have been shown to increase the common bile duct pressure. Fentanyl or sufentanil have no discernable effect on common bile duct diameter and may be preferable. Topical use of fentanyl Fentanyl has been used topically for painful skin ulcers. Drug preparations-Fentanyl

  • Patches 25, 50, 75, 100mcg/h (Durogesic) Starting dose: (25mcg/h) patch every 3 days
  • Inj. 50mcg/1ml, 100mcg/2ml, 500mcg/10ml Starting dose: 500mcg/24h CSCI
  • Lozenge with applicator 200, 400, 600, 800, 1200, 1600mcg (Actiq) Starting dose: 200mcg lozenge regardless of regular opioid dose

Alfentanil Alfentanil is a selective µ-receptor opioid agonist, similar to fentanyl. It is mainly metabolized in the liver to inactive compounds. It has been given by CSCI in a syringe driver, and appears to mix with most other commonly used drugs in palliative care. It should be diluted with water. Compared to fentanyl, an equianalgesic dose can be used in a much smaller volume, making CSCI of large doses possible. It is thus a useful substitute for fentanyl if CSCI use is desired. Alfentanil is rapidly eliminated and elimination appears unaffected by renal failure. Its onset is more rapid than for fentanyl. Its short-lasting effect means it has been used for incident pain (dressing change), but should not be used for breakthrough pain as it quickly wears off. Drug preparations-Alfentanil

  • Inj. 1mg/2ml, 5mg/10ml, 5mg/1ml Starting dose: 500mcg/24hCSCI (equivalent to diamorphine 5mg CSCI)

Sufentanil Sufentanil is a synthetic opioid very similar to fentanyl, but with more rapid onset and shorter duration of action. It can be used as an alternative to alfentanil if the fentanyl dose necessitates too large a volume for the portable syringe driver in use. It has also been used sublingually. The clinically-derived sufentanil to fentanyl relative potency is approximately 20:1. P.196
Methadone Methadone is a strong opioid analgesic, with several non-opioid actions. It differs from morphine/diamorphine in a number of ways:

  • δ-opioid receptor agonist
  • NMDA receptor antagonist
  • serotonin re-uptake inhibitor
  • long and variable elimination half-life
  • potential for numerous and complex drug interactions
  • inactive metabolites (lower toxicity in renal failure)

The first three of these actions may help account for reports of its effectiveness in managing neuropathic pain. The pharmacology of methadone is complex and very variable, so it must be used with specialist supervision. The commonest mistake is to underestimate its duration of action, since up to 10 days may be required to reach steady state plasma levels. The greatest tendency to accumulate the drug is in the elderly or those with liver failure. Drug interactions Methadone metabolism is increased by a number of other drugs, which when started could cause opioid withdrawal symptoms. Other interactions which inhibit metabolism can lead to overdose and toxicity.

Table 6a.3 Interactions which interfere with methadone metabolism
Decrease methadone levels Increase methadone levels
Phenytoin Fluconazole
Phenobarbitalno SSRIs
Carbamazepine (not sodium valproate or gabapentin)

Subcutaneous methadone Subcutaneous methadone has been used but there is a problem with skin reactions, partly because methadone in solution is acidic. If necessary to use, dilute as much as possible. In conversion of oral to subcutaneous or intravenous dosing, halve the dose of methadone. Use of methadone Indications

  • Pain only partially responsive to morphine e.g. inflammatory, ischaemic or neuropathic pain
  • Alternative opioid when side-effects develop with morphine (or other opioid)
  • Renal failure
  • Morphine tolerance—patients requiring ever increasing doses of morphine with no overall improvement in pain
  • Use with special caution in the elderly, COPD or asthma

Guidelines for use Note: Patients are rarely started on methadone for pain outside a specialist unit. The efficacy of methadone in comparison with morphine increases with chronic dosing and with higher dose. This is in part due to a long elimination half-life, and in part due to its non-opioid action. Many studies have shown the difficulty in converting doses between opioids and methadone. Several guidelines have been published. Morley and Makin guidelines are most commonly used in the UK, and are recommended for general use, and especially for patients switching opioid because of lack of effect. Guidelines (Morley and Makin 1998 Pain Reviews)

  • Stop all other opioids abruptly, i.e. do not reduce gradually
  • Loading dose of methadone. 1/10 of the 24h p.o. morphine or equivalent up to a maximum of 30mg
  • This same dose can be given as needed but not more frequently than 3-h
  • On day six, add the total dose of methadone given in last 48h, divide by four, and give at 12-h intervals, with provision for a similar or smaller dose q3h as required
  • Subsequent dose changes are by percentage increments as for morphine, every 4–6 days. [example 10mg b.d. → 15mg b.d.; 30mg b.d. → 40mg b.d.]
  • Re-assess carefully as accumulation can occur up to 10 days after methadone begun or dose changed

Side-effects All the typical opioid side-effects can be expected, although hallucinations and myoclonus are rare. Compared to morphine, methadone may cause less constipation, sedation and nausea. Methadone causes histamine release and can exacerbate asthma. It also has an antidiuretic effect. Drug preparations-Methadone

  • Mixture 10mg/ml
  • Mixture 1mg/ml
  • Tabs. 5mg; Linctus 2mg/5ml (for cough)

Topical opioids Opioids can act peripherally as analgesics, and there are a number of reports of their use on ulcerated skin, relieving pain and possibly inflammation. Morphine and diamorphine have been used most commonly, but fentanyl has also been reported. There have been no reports of systemic toxicity, and standard doses have been used, regardless of doses of systemic opioids taken simultaneously. Morphine or diamorphine 10mg may be mixed with sterile aqueous gel, a hydrocolloid gel (e.g. intrasite), or metronidazole gel, as appropriate. Apply once daily, and increase frequency if needed up to three times daily. P.198

  • Subcutaneous diamorphine is 3 times as potent as oral morphine.
  • Subcutaneous oxycodone is twice as potent as oral oxycodone.
  • Transdermal Fentanyl patches deliver 25,50,75 or 100mcg/h over three days. Peak plasma concentrations are achieved after 12–24h and a depot remains in the skin for some 24h after the patch is removed. Breakthrough doses of opioid will be necessary during the first 24h of application. One in ten patients who have had their pain controlled by morphine may experience a withdrawal reaction when converted to fentanyl. They may require oral morphine on a p.r.n. basis to manage the withdrawal symptoms for a day or two. A reduction of laxative may be necessary when converting from morphine to fentanyl.
  • Transdermal Buprenorphine delivers 35, 52.5 and 70 mcg/h over three days. No more than 140 mcg/h (two patches) should be used. Opioids other than buprenorphine can be used for breakthrough pain.
  • Transdermal Fentanyl and Buprenorphine should only be used where opioid requirements are stable.
  • Oral Transmucosal Fentanyl Lozenges (OTFC). For breakthrough pain in patients already on regular strong opioid therapy for chronic pain. Start titration at lowest dose (200 mcg) regardless of background opioid dose.
  • Topical opioids have been mixed with both metronidazole and hydrocolloid gels for the pain of skin wounds.


Table 6a.4 Equivalent opioid doses for step two and step three of the analgesic ladder
Oral medication
Opioid Step 2 mild to moderate pain Step 3 moderate to severe pain
Codeine 30–60mg q.d.s. Not applicable
Morphine i/r 2.5–5mg 4-h 10mg 4-h 20mg 4-h 30mg 4-h 40mg 4-h 60mg 4-h
Morphine m/r 5–15mg b.d. 30mg b.d. 60mg b.d. 90mg b.d. 120mg b.d. 180mg b.d.
Oxycodone i/r 1.5–3mg 4-6 h 5mg 4-h 10mg 4-h 15mg 4-h 20mg 4-h 30mg 4-h
Oxycodone m/r 5mg b.d. 10–20mg b.d. 30mg b.d. 40–50mg b.d. 60mg b.d. 90mg b.d.
Hydromorphone i/r Not applicable 1.3mg 4-h 2.6mg 4-h 3.9mg 4-h 5.2mg 4-h 6.5mg 4-h
Hydromorphone m/r Not applicable 4mg b.d. 8mg b.d. 12mg b.d. 16mg b.d. 20mg b.d.
Tramadol i/r Not applicable 50mg 4h Not applicable
Tramadol m/r 50mg b.d. 100–150mg b.d. Not applicable
Approximate 24 h oral morphine 10–30mg 60mg 120mg 180mg 240mg 360mg
In all opioid conversions there is uncertainly. If is safer to err on the side of underestimating analgesic requirements when converting between opioids but ensure that the patient has ready access to appropriate breakthrough analgesia. If in doubt about a conversion seek specialist advice if you are unfamiliar with the particular opioid.


Table 6a.5 Equivalent opioid doses for step two and step three of the analgesic ladder
Transdermal medication
Opioid Step 2 mild to moderate pain Step 3 moderate to severe pain
Fentanyl Not applicable 25 mcg/h every three days 50 mcg/h every three days 75 mcg/h every three days 100 mcg/h every three days
Buprenorphine 35 mcg/h every three days 52.5 mcg/h every three days 70 mcg/h every three days 2 × 70 mcg/h every three days Not applicable
Approximate 24 h oral morphine 15mg 60mg 120mg 180mg 240mg 360mg
In all opioid conversions there is uncertainty. It is safer to err on the side of underestimating analgesic requirement when converting between opioids but ensure that the patient has ready access to appropriate breakthrough analgesia. If in doubt about a conversion always seek specialist advice if you are unfamiliar with the particular opioid.


Table 6a.6 Equivalent opioid doses for step two and step three of the analgesic ladder
Subcutaneous medication
Opioid Step 2 mild to moderate pain Step 3 moderate to severe pain
Alfentanil CSCI (24h) 0.5–1mg 24h 2mg 24h 4mg 24h 6mg 24h 8mg 24h 12mg 24h
Diamorphine SC 24h p.r.n. 2.5–5mg 4-h 5–7.5mg 4-h 10mg 4-h 15mg 4-h 20mg 4-h
Diamorphine CSCI (24h) 5–10mg 24h 20mg 24h 40mg 24h 60mg 80mg 120mg
Morphine SC (4h p.r.n.) 2.5mg 5mg 10mg 15mg 20mg 30mg
Morphine CSCI (24h) 15mg 30mg 60mg 90mg 120mg 180mg
Oxycodone SC (4h p.r.n.) 2.5mg 4-h 5mg 4-h 7.5mg 4-h 10mg 4-h 15mg 4-h
*Oxycodone CSCI (24h) 5mg 24h 15–20mg 24h 30mg 24h 50mg 24h 60mg 24h 90mg 24h
Approximate 24 h oral morphine 30mg 60mg 120mg 180mg 240mg 360mg
In all opioid conversions there is uncertainty. It is a safer to err on the side of underestimating analgesic requirement when converting between opioid but ensure that the patient has ready access to appropriate breakthrough analgesia. If in doubt about a conversion seek specialist advice if you are unfamiliar with the particular opioid.
* The manufacturer of oxycodone states clearly that the conversion factor between oxycodone SC and diamorphine SC is 1:1. While most clinicians are comfortable with this ratio when converting from oxycodone SC to diamorphine SC, when converting from diamorphine SC to oxycodone SC some would advocate a 2:1 ratio with provision for breakthrough medication. As in every dose conversion the clinician must assess each individual patient and clinical situation.

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