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`Alternatives to Oral Opioids for Cancer Pain: Page 3 of 3
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`Review Article | February 01, 1999 | Palliative and Supportive Care
`
`By Sebastiano Mercadante, MD and Fabio Fulfaro, MD
`
`Oral Transmucosal Route
`
`The mouth has three areas for potential transmucosal delivery: sublingual, buccal, and gingival. Drug permeability appears to be
`
`highest in the sublingual area and lowest at the gingival site.[54]
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`The sublingual route has been proposed as a good route for the delivery of drugs because the
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`sublingual space is highly vascular and because this route avoids first-pass elimination. Sublingual
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`morphine has demonstrated very little kinetic advantage, however. Notable limiting factors include the
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`number of tablets that must be placed in the mouth as dose requirements increase, slow dissolution
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`http://www.cancernetwork.com/review-article/alternatives-oral-opioids-cancer-pain/page/0/3
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`Alternatives to Oral Opioids for Cancer Pain: Page 3 of 3 | Cancer Network
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`and absorption of the tablets, and dry mouth.[26,55] Transmucosal routes are not useful in patients
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`with severe cognitive failure or those in comatose states.
`
`Variations in Bioavailability
`
`Morphine is not readily absorbed in the mouth because of its low lipid solubility. The time to maximum
`
`concentration was significantly delayed after sublingual and buccal administration of morphine.[56]
`
`The bioavailability of sublingual morphine was 18%.[57]
`
`Compared to intravenous morphine, sublingual and buccal morphine resulted in delays in absorption
`
`and in the attainment of peak morphine and metabolite levels.[56] Sublingual morphine also produces
`
`a bitter taste.[58] Local toxicity, including rubor of the mucosa with pruritus and a burning feeling, was
`
`reported when a concentrated morphine solution was used to prevent swallowing and, hence, the first-
`
`pass effect.[59]
`
`Opioids with high lipid solubility, such as buprenorphine, fentanyl, and methadone, are absorbed to a
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`significantly greater extent than morphine when administered sublingually.[60] Buprenorphine has a
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`systemic bioavailability of about 50% after sublingual administration and is effective for long-term pain
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`management.[61] Methadone bioavailability was 38% with an increase up to 75%, when the oral
`
`cavity was buffered to a pH of 8.5 by adding bicarbonates.[57]
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`Sublingual fentanyl has been used as a rescue medication in doses of 25 mg (0.5 mL). The effect was
`Sublingual fentanyl has been used as a rescue medication in doses of 25 mg (0.5 mL). The effect was
`
`achieved within 1 minute and lasted 20 to 30 minutes. Fentanyl has an unpleasant taste, however,
`achieved within 1 minute and lasted 20 to 30 minute
`
`and increased fluid volume was a limiting factor because larger amounts were swallowed before
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`sublingual absorption. The sublingual use of a more potent opioid, such as sufentanil, is effective
`
`unless the volume of fluid becomes too great and patients have problems retaining the necessary
`
`volume of fluid in their mouth for some minutes.[60,62]
`
`Oral transmucosal fentanyl citrate (Actiq) is a fentanyl-containing matrix that dissolves when rubbed
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`against the buccal mucosa. When the matrix dissolves, approximately 25% of the total fentanyl is
`ves, approximately 25% of the total fentanyl is
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`absorbed almost immediately through the buccal mucosa and enters the bloodstream with no first-
`absorbed almost immediately through the buccal mu
`
`pass metabolism, producing a rapid effect. The remaining 75% is swallowed, thus undergoing first-
`
`pass metabolism. About one-third of this amount is bioavailable, achieving a total bioavailability of
`
`about 50%.[60]
`
`Transmucosal fentanyl provides a rapid onset of pain relief within 5 to 10 minutes and a short duration
`
`of effect, even though it takes more than 20 minutes to achieve peak plasma levels with this route.[63]
`
`These characteristics make transmucosal fentanyl appropriate for treating breakthrough pain
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`episodes.[64] and this formulation was recently approved by the FDA for this purpose in adult cancer patients.
`
`Intranasal Analgesic Device
`
`A device for patient-controlled intranasal analgesia was recently reported to provide a rapid onset of action and an analgesic effect
`
`equivalent to intravenous administration. The high bioavailability after the intranasal application of lipophilic opioids seems to be due to
`
`the fact that the venous outflow of the nasal mucosa enters the systemic circulation, bypassing the liver.[65]
`
`Theoretically, intranasal morphine is an attractive way of rapidly delivering analgesic agents through the highly vascular areas of the
`
`nasal cavity. No studies exist, however, to support this route for analgesia. In addition, serious local toxicity has been reported.[59]
`
`Inhalational Route
`
`Nebulization is an inefficient way of administering drugs, as bioavailability has been shown to be very low.[66] Since the airways have
`
`been shown to contain opioid receptors, a local mode of action has been proposed for nebulized opioids. Nebulized therapy has been
`
`used to administer several drugs exerting a local action in the airways. The rationale for using morphine by this route is that it acts
`
`locally and directly on afferent nerve endings in the lung to reduce dyspnea, rather than systematically.
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`The effects of nebulized therapy have been described in different groups of patients, including those with cancer, using different
`
`opioids at varying dosages. Extremely ill patients, those in comatose states, or those suffering from asthma and feelings of
`
`claustrophobia caused by wearing a mask to inhale the drugs, cannot use this route. An acute respiratory depression requiring
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`http://www.cancernetwork.com/review-article/alternatives-oral-opioids-cancer-pain/page/0/3
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`Alternatives to Oral Opioids for Cancer Pain: Page 3 of 3 | Cancer Network
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`ventilation was recently reported after 4 mg of nebulized morphine was administered to a dyspneic patient receiving chronic opioid
`
`morphine.[67]
`
`Conclusions
`
`Although the oral administration of analgesic agents to manage cancer pain is generally preferred because of its ease and reliability,
`
`many patients require alternate routes during the course of their illness. These alternative routes are likely to be useful for patients
`
`unable to use the oral route because of bowel obstruction, severe vomiting, dysphagia, cognitive failure, or comatose states.
`
`Pharmacokinetic data and clinical experience also suggest that, in some clinical situations, routes of opioid administration other than
`
`the oral route have potential advantages.
`
`Table 1 summarizes some of the potential clinical applications of the different alternative routes.
`
`Previous
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`Page: 1 2 3
`
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`http://www.cancernetwork.com/review-article/alternatives-oral-opioids-cancer-pain/page/0/3
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