Although the optimal route of administration of opioids is by mouth, some patients may require alternative routes during the course of their illnesses for several reasons. These include bowel obstruction, severe emesis, or severe dysphagia. In these cases, the alternatives include the subcutaneous or rectal route. The transdermal route also provides a simple, comfortable method that produces stable blood drug concentrations. The high potency and lipid solubility of fentanyl make it suitable for this route of administration. Iontophoresis can provide a rapid drug delivery rate, but no clinical studies exist to document the long-term effectiveness of this method in controlling pain. The transmucosal route is recommended only for those opioids with high solubility, such as buprenorphine, the fentanyl series, and methadone. Oral transmucosal fentanyl (Actiq) provides a rapid onset of pain relief and is appropriate for treating episodes of breakthrough pain. [ONCOLOGY 13(2):215-225, 1999]
Most patients with cancer pain respond to the oral administration of analgesic drugs given regularly to prevent recurrence of pain. The optimal route of administration of opioids is by mouth. Studies have shown that oral opioids can often be continued until, or near to, death.[1,2]. However, some patients, may be unable to take drugs orally because of bowel obstruction, severe emesis, or severe dysphagia due to neurologic impairment or drowsiness. In these cases, the preferred routes of opioid administration are the subcutaneous and rectal routes..
When adverse effects prevail with oral opioid administration, the analgesic response may be improved by changing the route of administration. In a survey documenting the strategies used by pain control physicians to select opioid drugs and routes of administration, the route of administration was changed in 61% of cases because of convenience or because of discomfort or complications with the original route. Changing the route of administration achieved better pain control with fewer adverse effects. At the time of discharge, transdermal and intravenous routes were each chosen for 18% of the cases and subcutaneous routes for 5%. Approximately 70% of patients benefited from the use of an alternative route for opioid administration for hours, days, or months before death.
This review presents the principal indications and contraindications for the most common alternative routes to oral opioid administration for the relief of cancer pain. These alternative routes—subcutaneous, rectal, transdermal, oral transmucosal, and inhalational—do not require close supervision and can be used for most patients at home.
Although the intravenous route allows patients to receive a continuous infusion of opioids, it is complicated to maintain. Also, since this route requires prolonged venous access and close supervision, it may prevent many patients from returning home.
Continuous intravenous infusion may continue to have a role in cases in which large volumes of opioids are administered. In most other cases, the subcutaneous route should be considered the standard alternative systemic route. The main indications for using the subcutaneous route are vomiting, bowel obstruction, dysphagia, comatose state, breakthrough pain, and initial titration with frequent dose changes.
The ability to provide subcutaneous infusions in the home has had a profound impact on patient care. Before beginning this approach, patients and caregivers need to consider the choice of pump, drug, mode of infusion, dosing schedule, family and community health-care system resources, and cost.
A plastic cannula can be easily inserted in the patient’s anterior chest or abdomen to avoid multiple injections. When opioids are administered by a parenteral route, there is a short time to peak analgesic effect, which facilitates a more rapid dose adjustment.
The continuous subcutaneous infusion of opioids has been shown to be effective in the treatment of pain from advanced cancer. It may reduce the peaks and valleys in plasma opioid concentrations inherent in intermittent administration.
The subcutaneous route has been shown to be equianalgesic to the intravenous administration of morphine when administered as a continuous infusion. Pharmacokinetic studies have demonstrated that subcutaneous and intravenous infusions of identical doses of both morphine and hydromorphone produced no difference in plasma opioid concentrations [9,10], and that both provide satisfactory analgesia with comparable adverse effects. The absorption at higher doses may differ, however, and this may account for the possible need for dose increases with subcutaneous infusions.
Studies have also shown that subcutaneous morphine provided effective analgesia with less severe nausea and vomiting in patients who did not achieve satisfactory analgesia with oral morphine.[11,12] No significant differences were detected in either pain relief or adverse effects between subcutaneous and epidural administration. The ratio between subcutaneous and epidural morphine was close to 3:1, although the conversion ratios should be individually determined and may vary from 1 to 10. A recent paper indicates that there is no significant benefit to be gained from administering morphine intrathecally rather than subcutaneously, but further data are needed to confirm this preliminary observation.
Reducing Adverse Effects
Adverse effects reported with oral administration of morphine can be reduced by administering the drug through the subcutaneous or the epidural route. This observation has been attributed to the lower metabolite/morphine ratios reported with parenteral rather than oral administration of morphine, demonstrating that morphine metabolism is significantly lower during parenteral than during oral administration.
In a survey of cancer patients followed at home, the preferred alternative route to oral administration of opioids was the subcutaneous route, while the intravenous route was most often used in patients who already had central vascular access. Subcutaneous administration was rarely being employed at the time of referral for home care, but was chosen for short periods, mainly in the last week of life, due to neurologic derangement, nausea and vomiting, or analgesia side effects.
Although continuous subcutaneous infusion offers stable blood drug levels, it has not been shown to control pain more effectively than intermittent administration, which is a very simple technique that does not require infusors or pumps. Intermittent injections of subcutaneous morphine are safe and effective in decreasing the intensity of dyspnea without modifying oxygen saturation, respiratory rate, or the end tidal pCO2.
During the steady-state administration of subcutaneous morphine, there is a large interindividual variation in plasma morphine, with a poor relationship to the daily administered dose. Measurements of morphine, morphine-3-glucuronide, and morphine-6-glucuronide in cerebrospinal fluid did not show any overt relationship to analgesia or side effects. The prevalence of myoclonus among patients receiving oral morphine was threefold higher than among those receiving parenteral morphine. Neither myoclonus nor cognitive impairment, however, was significantly associated with the morphine-6-glucoronide/morphine ratio after adjustments were made for other variables.
Drugs Used Subcutaneously
Hydromorphone has been safely administered subcutaneously, and reports indicate that it results in pain control and toxicity similar to morphine. Because hydromorphone is more soluble than morphine, it can be administered in higher daily doses in very low volumes. The limited capacity of subcutaneous tissue to absorb fluid is a relevant advantage when patients need very high doses of opioids.
Fentanyl has also been used both intravenously and subcutaneously in patients who have refractory cancer pain.[18-20] Subcutaneous starting doses ranged from 100 to 1,000 mg/d.
When the fentanyl dose needed was too large for the portable syringe driver being used, the more potent opioid sufentanil (Sufenta) was substituted. The clinically derived mean relative potency of fentanyl to morphine infusions was 68:1, whereas the potency of su-fentanil relative to fentanyl was about 20:1.
A patient with acute renal impairment and bowel obstruction was successfully treated with a subcutaneous continuous infusion (25 mg/h) of fentanyl and 12.5-mg boluses for the last days of life. This limited the worsening of the patient’s dramatic clinical picture of bowel obstruction combined with renal failure. Plasma drug level ranged from an initial detectable value of 0.12 ng/mL to a maximum of 1.04 ng/mL.
No local toxicity of subcutaneous fentanyl has been reported. No formal pharmacokinetic studies of the subcutaneous infusion of fentanyl have yet been conducted.
Minor erythema or thickening at the injection site has been reported in 52% of patients using regular subcutaneous bolus morphine via an indwelling cannula, and more severe local reactions occurred in 4% of patients. Local toxicity requiring frequent site changes seems to be unrelated to dose, opioid used, duration of site use, triceps skin fold, age, or gender. Adverse skin reactions have been reported with the use of subcutaneous methadone, seeming to contraindicate continuous subcutaneous infusion of this agent. The use of the subcutaneous route is problematic in patients with coagulation disorders, severe immunosuppression, fluid retention at the infusion site, or low skin perfusion.[3,5]
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