Selecting the Appropriate Route of Systemic Opioid Administration

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Opioids should be administered by the least invasive and safest route capable of providing adequate analgesia.

Non-Invasive Routes

The oral route of opioid administration is the preferred approach in routine practice. Alternative routes are necessary for patients who have impaired swallowing or gastrointestinal dysfunction, those who require a very rapid onset of analgesia and those who are unable to manage either the logistics or side effects associated with the oral route. For highly tolerant patients, the inability to prescribe a manageable oral opioid programme due to an excessive number of tablets or volume of oral solution may be an indication for the use of a non-oral route. For patients who do not require very high opioid doses, non-invasive alternatives to the oral route of opioid administration include the rectal, transdermal and sublingual routes. Rectal suppositories containing oxycodone, hydromorphone, oxymorphone and morphine have been formulated and controlled-release morphine tablets can also be administered per rectum. The potency of opioids administered rectally is believed to approximate oral administration. Fentanyl is the only opioid available as a transdermal preparation. The fentanyl transdermal system consists of a drug reservoir that is separated from the skin by a copolymer membrane that controls the rate of drug delivery to the skin surface such that the drug is released into the skin at a nearly constant amount per unit time. There is some interindividual variability in fentanyl bio-availability by this route and this phenomenon, combined with large differences in elimination pharmacokinetics, necessitates dose titration in most cases. Transdermal patches capable of delivering 25, 50, 75 and 100 mg/h are available. Multiple patches may be used simultaneously for patients who require higher doses. At the present time, the limitations of the transdermal delivery system include its cost and the requirement for an alternative short-acting opioid for breakthrough pain. Sublingual absorption of any opioid could potentially yield clinical benefit, but bio-availability is very poor with drugs that are not highly lipophilic and the likelihood of an adequate response is consequently low. Sublingual bupre-norphine, a relatively lipophilic partial agonist, can provide adequate relief of mild to moderate postoperative pain. Both fentanyl and methadone are relatively well absorbed through the buccal mucosa and sublingual administration of an injectable formulation is occasionally performed in the relatively opioid-naive patient who transiently loses the option of oral dosing. Overall, however, the sublingual route has limited value due to the lack of formulations, poor absorption of most drugs and the inability to deliver high doses or prevent swallowing of the dose. An oral transmucosal formulation of fentanyl, which incorporates the drug into a candy base, is under evaluation. Studies in cancer patients suggested that it is useful and that it can provide rapid and very effective relief of breakthrough pain.

Invasive Routes

For patients undergoing a trial of systemic drug administration, a paren-teral route must be considered when the oral route is precluded or there is need for rapid onset of analgesia, or a more convenient regimen. Repeated parenteral bolus injections, which may be administered by the intravenous (IV), intramuscular (IM) or subcutaneous (SC) routes, may be useful in some patients but are often compromised by the occurrence of prominent 'bolus' effects (toxicity at peak concentration and/or pain breakthrough at the trough). Repetitive IM injections are a common practice, but they are painful and offer no pharmacokinetic advantage; their use is not recommended. Repeated bolus doses without repeated skin punctures can be accomplished through the use of an indwelling IV or SC infusion device. To deliver repeated SC injections, a 27-gauge infusion device (a 'butterfly') can be left under the skin for up to a week. Intravenous bolus administration provides the most rapid onset and shortest duration of action. Time to peak effect correlates with the lipid solubility of the opioid and ranges from 2-5 minutes for methadone to 15-30 minutes for morphine and hydromorphone. This approach is commonly applied in two settings:

1. to provide parenteral opioids to patients who already have venous access and are unable to tolerate oral opioids;

2. to treat very severe pain, for which IV doses can be repeated at an interval as brief as that determined by the time to peak effect, if necessary, until adequate relief is achieved.

Continuous parenteral infusions are useful for many patients who cannot be maintained on oral opioids. Long-term infusions may be administered IV or SC. In practice, the major indication for continuous infusion occurs among patients who are unable to swallow or absorb opioids. Continuous infusion is also used in some patients whose high opioid requirement renders oral treatment impractical. Continuous SC infusion is often used for ambulatory postoperative patients. A range of pumps is available, which vary in complexity, cost and ability to provide patient-controlled 'rescue doses' as an adjunct to a continuous basal infusion. Opioids suitable for continuous SC infusion must be soluble, well absorbed and non-irritant. Experience has been reported with heroin, hydromorphone, oxymorphone, morphine and fentanyl. Methadone appears to be relatively irritating and is not recommended. To maintain the comfort of an infusion site, the SC infusion rate should not exceed 5 cc/hr. Patients who require high doses may benefit from the use of concentrated solutions. In selected cases, concentrated opioid solutions can be compounded specifically for continuous SC infusion. Subcutaneous infusion, like repeated SC bolus injections, can usually be administered using a 27-gauge 'butter-fly' needle. The infracla-vicular and anterior chest sites provide the greatest freedom of movement for patients, but other sites may be used. A single infusion site can usually be maintained for 5-7 days. Occasional patients develop focal erythematous swelling at the site of injection; this appears to be a common complication with methadone and has also been described with morphine and hydro-morphone. Continuous SC delivery of drug combinations may be indicated when nausea, anxiety or agitation accompanies pain. An antiemetic, neu-roleptic or anxiolytic may be combined with an opioid, provided that it is non-irritant, miscible and stable in combined solution. Experience has been reported with metoclopromide, haloperidol, scopolamine, cyclizine, metho-trimeprazine, chlorpromazine and midazolam. In some circumstances, continuous IV infusion may be the most appropriate way of delivering an opioid. The need for very large doses, or treatment with methadone, may suggest the utility of this approach. If continuous IV infusion is to be continued on a long-term basis, a permanent central venous port is recommended.

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