Alternatives to Oral Opioids for Cancer Pain

Transcription

1 Alternatives to Oral Opioids for Cancer Pain Review Article [1] February 01, 1999 Palliative and Supportive Care [2] By Sebastiano Mercadante, MD [3] and Fabio Fulfaro, MD [4] 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 Introduction 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.[3]. 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%.[4] Approximately 70% of patients benefited from the use of an alternative route for opioid administration for hours, days, or months before death.[5] 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. Subcutaneous Route 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. Multiple Benefits 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.[6] 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.[4] 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.[7] The subcutaneous route has been shown to be equianalgesic to the intravenous administration of morphine when administered as a continuous infusion.[8] Pharmacokinetic studies have demonstrated that subcutaneous and intravenous infusions of identical doses of both morphine and Page 1 of 10

2 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.[8] 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[13] 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.[14] 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.[2] 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 pco 2.[15] 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.[16] 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.[17] 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.[6] 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.[19] 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.[20] No formal pharmacokinetic studies of the subcutaneous infusion of fentanyl have yet been conducted. Side Effects/Contraindications 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.[11] Local toxicity requiring frequent site changes seems to be unrelated to dose, opioid used, duration of site use, triceps skin fold, age, or gender.[21] Adverse skin reactions have Page 2 of 10

3 been reported with the use of subcutaneous methadone, seeming to contraindicate continuous subcutaneous infusion of this agent.[22] 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] Rectal Route The rectal route of opioid administration can be considered an alternative to the oral route in patients with nausea, vomiting, dysphagia, bowel obstruction, or malabsorption. Because rectal administration may avoid the need for portable pumps or needle insertion, this route may also be an alternative to parenteral injections or infusions in patients with bleeding disorders or generalized edema, to control breakthrough pain episodes, or when infusion techniques are not available.[5] Absorption of Drugs The rectal absorption of drugs occurs mostly by passive diffusion. Potentially, rectal administration has the pharmacokinetic advantage of bypassing first-pass hepatic metabolism by allowing the drug to enter the systemic circulation via lower rectal veins. Using a small amount of liquid may prevent diffusion of the drug and avoid drainage by the superior rectal vein into the portal system. Although the avoidance of first-pass metabolism depends on the level of absorption within the rectum, there is no clear anatomic demarcation between portal and systemic drainage because of the presence of extensive anastomoses. This makes it difficult to predict what proportion of the drug will be absorbed via the portal vein. Rectal administration cannot be directly equated with the administration of drugs into stomas, since drugs administered into stomas go directly and primarily into the portal circulation, potentially maximizing any first-pass metabolism.[23] The absorption of drugs administered rectally also depends on the preparation (aqueous or alcoholic solutions, suppositories, use of surfactants), ph of solutions used, and the presence of feces in the rectal ampulla. Variations in Bioavailability As expected, considerable interindividual variation has been reported with respect to the bioavailability of morphine administered rectally.[23,24] In a study among patients with acute pain, rectal morphine had a faster onset of action and a longer duration of efficacy compared to a similar dose of oral morphine. This rapid peak effect may be useful in managing breakthrough pain when pumps are unavailable, or in the home setting where injections may be problematic. This type of administration is inadvisable for daily prolonged treatments, however, because it is uncomfortable to patients.[25] Large variabilities in absorption reported with the sustained-release morphine preparations are presumably the result of differing conditions of local hydration, since the release mechanism is dependent on hydration.[26] Using controlled-release formulations, equivalent analgesia was maintained switching from oral to rectal morphine. The dose had to be decreased, however, because patients reported drowsiness.[27] High- and low-viscosity controlled-release suppository formulations of morphine were significantly more bioavailable than a reference formulation administered orally. The time to peak plasma morphine concentration was significantly delayed and peak blood levels from rectal dosing were lower than those from oral dosing.[28,29] Considerable interpatient variability has been reported in the absorption and metabolism of rectal sustained-release morphine.[24] Much higher metabolite concentrations were reported after oral morphine than after rectal administration, although the ratio between morphine-3-glucuronide and morphine-6-glucuronide remained the same after either route.[30] These studies show that rectal morphine is absorbed into the systemic circulation at least as readily as is oral morphine. This means that patients receiving oral morphine can be switched to the same dose of rectal morphine, although some patients may require a small reduction in dose due to drowsiness, as mentioned above.[23] Drugs Used Rectally Rectal administration of oxycodone (Percolone) appears to be comparable to oral administration.[31] After a microenema of a liquid preparation of methadone (10 mg), pain relief was significant after 30 minutes and lasted longer than 8 hours in opioid-naive patients with cancer pain.[32] In cancer patients with poor pain control receiving high doses of subcutaneous hydromorphone, the differences found between oral (capsules) and rectal (suppositories) doses of methadone suggest a greater bioavailability with the oral route, although similar analgesic effects were achieved.[33] A wide interindividual variability in pharmacokinetics was also observed, just as has been seen with Page 3 of 10

4 the oral and intravenous routes.[32] Side Effects/Contraindications The rectal route requires a functional anal sphincter. Patients with diarrhea, a colostomy, hemorrhoids, anal fissures, or neutropenia are not candidates for the rectal administration of opioids. Patients with advanced cancer being treated at home have found the rectal route uncomfortable. Rectal formulations of opioids are not commercially available in most European countries,[34] and progressive titration can be difficult. Mild mucosal hyperemia was observed in approximately 40% of patients treated with rectal opioids. Prolonged use is inadvisable not only because it is uncomfortable but also because the presence of fecal matter or the expulsion of the suppository by bowel movements may result in further variability in drug absorption and, hence, in clinical effects. Transdermal Route The transdermal administration of opioids provides a simple, noninvasive alternative that produces stable blood drug concentrations comparable to those achieved with continuous infusion. Although morphine is highly polar and does not easily penetrate human skin, the low molecular weight, high potency, and lipid solubility of fentanyl make it suitable for delivery via the trans-dermal therapeutic system (TTS [Duragesic]). The amount of fentanyl released per hour is proportional to the surface area of the TSS patch on the skin. Commercial dosing systems are available that provide delivery rates of 25, 50, 75, and 100 µg/h. Depot Accumulation At the start of fentanyl TTS treatment, depot accumulation of the drug results in a significant delay between the time that the initial patch is applied and the time that clinical relevant plasma drug levels are achieved. Approximately half of the cancer patients using TTS require concomitant use of short-acting opioids during the titration period. This delayed onset of action is not problematic with repeated dosing. The pharmacokinetics of this system suggest that serum levels of fentanyl can be maintained long enough to provide constant analgesia for 72 hours, with small fluctuations in serum level after the second application.[35] Due to dermal depot accumulation of fentanyl, serum half-life is greater than16 hours.[36] Conversion Ratios Patients who have malignancies of the head and neck region or of the gastrointestinal tract frequently present with symptoms such as dysphagia, severe nausea and vomiting, or constipation that require parenteral or nonoral administration of opioids.[37] Controversy exists over how to safely and effectively switch from oral morphine to fentanyl TTS,[38] since approximately 50% of patients will require an increase in dose soon after switching, based on the manufacturer s conservative recommendations for a morphine/fentanyl TTS conversion ratio of 150:1. To complicate the situation, other opioids first need to be converted to parenteral morphine equivalents, although it is now recognized that using a standard conversion table results in incorrect doses for some drugs.[39] Because the use of morphine for the titration of transdermal fentanyl is time-consuming, the use of intravenous patient-controlled analgesia with fentanyl has been proposed, using a conversion ratio of 1:1.[40] This conversion ratio, however, was found to be too low, as demonstrated by increasing pain intensity and increasing supplementary morphine requirements. A revised ratio of 1:1.5 may still pose serious problems by being too low in the majority of patients but dangerously high in others.[41] The conversion from oral morphine to transdermal fentanyl has been demonstrated to be effective and safe, however. Patients with a stable, low level of cancer pain were initially switched from oral morphine to transdermal fentanyl using a 100:1 ratio. In 42% of the patients, however, this initial 100:1 ratio produced inadequate analgesia,[42] suggesting that the time needed to determine the optimal dose might be prolonged when compared to conventional administration routes. After adjusting the dosage according to the patients needs, a mean morphine/transdermal fentanyl ratio of 70:1 was established. Aggressive titration produced by changing patch size every 24 hours has been proposed to increase plasma fen-tanyl levels more rapidly.[43,44] On the other hand, adherence to recommended starting doses and the judicious use of a short-acting opioid analgesic during the titration phase have been advocated to avoid the risk of overdosage.[45] For some patients, concerns about limited Page 4 of 10

5 cross-tolerance, advanced age, or sensitivity to opioids should also be addressed. Benefits of TTS Therapy It has been suggested that with the first application of transdermal fentanyl, the patient should receive the last application of a long-acting opioid (methadone or sustained-release morphine), leaving a short-acting opioid to serve as rescue medication during the first days of titration.[42] Studies comparing transdermal fentanyl with oral morphine indicate that pain control was similar, although a higher use of rescue medication has been reported in patients who were receiving fentanyl-tts therapy.[42,46] The quality of sleep and morning vigilance were improved and patients experienced less nausea, vomiting, and constipation with fentanyl-tts.[47] A lower concentration of a more potent opioid, such as fentanyl, is likely to provide less stimulation to both the chemoreceptor trigger zone, which is outside of the blood-brain barrier, and to the receptors in the gastrointestinal tract, resulting in less interference with peristalsis.[48,49] Constipation, daytime drowsiness, and laxative use decreased significantly during fentanyl therapy. Most patients preferred fentanyl TTS over oral morphine.[42,43,46] Side Effects/Contraindications There are case reports of withdrawal syndromes associated with conversion from oral opioids to a transdermal system, despite adequate pain control.[46] Gastrointestinal symptoms are more frequent with a transdermal system, probably because morphine and fentanyl have different affinities for opioid receptors in the gut or because of their different pharmacokinetic properties.[49-51] Cutaneous reactions tothe patch, including erythema and itching, are generally rare, mild, and transient.[52] The transdermal route is likely to be less useful in patients with generalized edema. Increased skin temperature may cause drugs to be absorbed too rapidly. The slow pharmacokinetics of transdermal systems make them appropriate only for patients with a relatively stable pain condition. Therefore, patients who have unstable pain, require rapid titration of the analgesic dose, or need frequent dose changes are not candidates for transdermal systems. High dosage requirements are a limiting factor in cachectic and pediatric patients, since fentanyltts dosage is limited by the area of application. Limited Use of Iontophoresis Iontophoresis, a method of transdermal administration of ionized drugs, uses an external electrical field to propel electrically charged molecules through the skin. The rate of drug delivery is proportional to the current intensity, allowing for rapid achievement of therapeutic plasma drug levels. Iontophoresis can deliver morphine systemically in high enough concentrations to provide pain relief, even though morphine is a polar molecule that has difficulty passing through the skin. [53] When used with fentanyl in a study among volunteers, iontophoresis produced an effective plasma fentanyl concentration in half the time when the electric dose (ma/min) was doubled. This double dose also doubled the area under the curve and the peak plasma concentration.[54] There are no clinical studies of how this method fares over prolonged periods or in the control of cancer pain. 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] The sublingual route has been proposed as a good route for the delivery of drugs because the sublingual space is highly vascular and because this route avoids first-pass elimination. Sublingual morphine has demonstrated very little kinetic advantage, however. Notable limiting factors include the number of tablets that must be placed in the mouth as dose requirements increase, slow dissolution and absorption of the tablets, and dry mouth.[26,55] Transmucosal routes are not useful in patients 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] Page 5 of 10

6 Opioids with high lipid solubility, such as buprenorphine, fentanyl, and methadone, are absorbed to a significantly greater extent than morphine when administered sublingually.[60] Buprenorphine has a systemic bioavailability of about 50% after sublingual administration and is effective for long-term pain 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] 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, and increased fluid volume was a limiting factor because larger amounts were swallowed before 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 against the buccal mucosa. When the matrix dissolves, approximately 25% of the total fentanyl is absorbed almost immediately through the buccal mucosa and enters the bloodstream with no first-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 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. 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 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. References: 1. Lombard DJ, Oliver DJ: The use of opioid analgesics in the last 24 hours of life of patients with advanced cancer. Palliat Med 3:27-29, Page 6 of 10

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