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Palliative Care Perspectives : Chapter 4: Pain Management : Specific Opioids

Available medications can be classified by their durations of action. Short-acting opioids can be administered alone or in combination with another analgesic, most commonly acetaminophen. Long-acting medications either have a long serum half-life or a delivery vehicle that allows less frequent administration. A distinction between "strong" and "weak" opioids is less useful. opioids are similarly efficacious when given in adequate doses.

Short-acting agents are useful for the treatment of rapidly changing pain, such as acute pain and bursts of pain that occur with chronic pain. A short half-life allows rapid titration both up and down. The disadvantages of these agents also relate to their short half-lives. Frequent administration, if given around the clock, can make compliance difficult. Rapid changes in serum drug levels occur. Certain side effects, such as sedation, nausea, and euphoria, are more strongly related to changes in serum levels than to absolute blood levels. Thus, when taken intermittently patients may experience proportionately more side effects with these agents than with comparably dosed long-acting agents.

Long-acting agents either have long half-lives (methadone) or mechanisms for sustained delivery of a short-acting agent (sustained release morphine, hydrocodone, or oxycodone and fentanyl patches). Sustained-release preparations have the advantage of allowing more frequent titration of doses (as the agents' pharmacologic half-lives are short) with the convenience of infrequent dosing. Sustained-release preparations may be safely adjusted after 24 hours. They also may result in smoother opioid blood levels, thereby minimizing side effects.

Morphine

Morphine can be given as soluble tablets, as an elixir, as rectal suppositories, subcutaneously (SC), intravenously (IV), and intramuscularly (IM). While the elixir form is convenient for patients unable to swallow pills, its bitter taste is a problem for some. Morphine has a strong "first pass effect" when given orally. Thus, the oral to parenteral potency ratio is given as 6:1 for a single dose. With chronic administration, this first pass effect lessens, and the oral to parenteral potency ratio is 3:1. It is metabolized in the liver and excreted with active metabolites by the kidneys. The metabolite morphine 6-glucuronide's half-life is particularly prolonged in renal failure. Thus, kidney failure can result in significant drug accumulation of this active metabolite.18 Although controlled studies comparing different opioid use in renal failure have not been done, many experts recommend that morphine be avoided in such cases.19 Morphine can cause histamine release, resulting in itching or, rarely, more severe allergic symptoms, although the extent to which this occurs more frequently than with other opioids is debated.9,20-22 As Katcher notes, the mechanism of morphine-related itching may not always be due to histamine release.23

Although histamine release can be a mechanism of true allergy to morphine, more common and clinically important is a "psychological allergy." Having vomited in the past with morphine or simply out of a fear of the drug's reputation, certain patients are very resistant to the use of morphine. In such cases alternatives should be tried.

Tablet sustained-release (SR) morphine is regular morphine given in a slow-release pill form. Because the morphine is in a special waxlike matrix, these pills cannot be crushed, which limits their use in patients who cannot take pills. The lowest dose available is 15 mg. They can be given two to three times a day. The great advantage of these agents is that they combine the best of both worlds: a pharmacologically short serum half-life and twice daily or TID administration. This allows rapid titration of dose. Slow release morphine is relatively inexpensive compared to short-acting morphine.

Kadian is a new form of SR morphine in capsule form with morphine placed inside very small polymeric beads (20 to 100 mg).24 It is possible to give Kadian capsules only once a day, although patients may require BID dosing. Kadian is expensive but may offer an advantage when enteral morphine administration is desired and patients are unable to swallow pills. The capsule can be opened and sprinkled onto food, such as applesauce, or the beads may be flushed through a gastric-tube. Because of the expense involved, for stable pain methadone, which can be administered as a liquid, is generally preferred in such situations (see below).

If a patient taking slow release morphine becomes nauseated for whatever reason or is unable to take the medication orally, SR morphine can be administered rectally with approximately 90% to 100% of oral efficacy.9 This may be of help in an emergency. Because of possible discomfort, long-term SR morphine via the rectum is not usually recommended.

Palliative Care Note
In an emergency with patients on SR morphine who become unable to swallow, the tablet can be administered rectally with reasonable absorption, allowing time for clinicians to identify an alternate delivery route.

Generally speaking morphine is the drug of choice for parenteral administration unless side effects become apparent or very high doses (usually greater than 30 mg/h) are to be given subcutaneously (as the volume of administration may become too great for efficient SC administration).

Hydromorphone

hydromorphone is similar to morphine in duration of action but is approximately five to seven times as potent. When administered orally it can be given in pill form, as an elixir, or as a rectal suppository. An advantage of hydromorphone is that the name does not evoke the strong emotional reactions of morphine.

hydromorphone is the drug of choice for subcutaneous administration of a high dose of opioid, as it can be delivered in a very concentrated form. It is also the drug of choice when using parenteral opioids in a patient with renal failure or when rotating a patient who is experiencing agitation and myoclonus off morphine.

A slow-release formulation of hydromorphone is available in some countries (not yet the United States). It may serve as a useful alternative to morphine and oxycodone. Angst demonstrated that this agent is effective, although the time to peak-effect is prolonged, approximately 9-12 hours, significantly longer than sustained release morphine or oxycodone preparations (3-6 hours).25,26

Oxycodone

Short-acting forms of oxycodone (without acetaminophen) are now available in pill and liquid form. Oxycodone is approximately 1.5 times as potent on a milligram to milligram basis compared to chronic use morphine. It is more expensive than morphine.

SR oxycodone is quite similar to SR morphine in dosage and dosing intervals. SR oxycodone 10 mg q12h is roughly the same as two Percocet tablets (5mg oxycodone/325mg acetaminophen strength) spread over 12 hours. Histamine release appears to be less of a problem than with morphine. Oxycodone should be considered for patients who experience pruritus on morphine and when an oral SR agent is needed in the presence of significant renal failure. It has been argued that oxycodone produces fewer mental status changes than does morphine. This may be a reason for using the drug when mental status changes are attributed to morphine.27 Other studies have not demonstrated significant differences in side effects between long-acting oxycodone and morphine.28 However, large controlled trials of the two situations in which an advantage for oxycodone over morphine has been suggested (in significant renal failure and in patients with delirium or at very high risk for delirium) have not been performed.

Palliative Care Note
When ordering SR morphine or oxycodone, write the dosing interval as "q12h," not "BID." (In many institutions BID medications are not given q12h.

SR oxycodone can offer a great psychological advantage in overcoming "opioid-phobia" in patients and health care providers. It may be easier to achieve compliance if it is explained that it is the same active ingredient found in Percocet. The oxycodone is just "spread out" over 12 hours. Unfortunately, there have been reports in the United States of SR oxycodone becoming a drug of choice for opioid abusers, who crush the drug and then take it. Pharmacologically, I know of no reason why oxycodone would have any more or less addictive potential than does any other opioid. Thus, a new wave of opioid-phobia is arising in response to this recent fad of addicts, which may inappropriately limit the use of this agent when otherwise indicated. SR oxycodone is significantly more expensive than is SR morphine. Its use instead of morphine should be justified on a case-by-case basis.

Methadone

Methadone has a long half-life, which allows it to be used on a BID or TID schedule for most patients. It can be given in liquid form and is thus useful in patients who have an enteral route of administration when they are unable to take pills or have a feeding tube. Methadone is cheap. The major problem with methadone is its long half-life. It cannot be rapidly titrated up or down, as it takes days to achieve stable serum levels. Thus, methadone is not indicated in the treatment of rapidly changing pain. Low-dose methadone can be an excellent and inexpensive agent for patients with stable, low-grade, chronic pain. As a rule of thumb, the dose of methadone should not be increased any more rapidly than every three days to avoid possible stacking of doses.* In addition to direct opioid receptor agonist effects, methadone blocks n-methyl-D-aspartate (NMDA) receptors, which may be helpful in refractory pain syndromes.29,30

* This rule of thumb assumes simple escalation of methadone. Various schemes for converting other opioids to methadone have been described, including gradual daily decreases in prior opioid doses and daily equivalent increases in methadone over a period of days. (As described in a talk by L. Friedman, "Using Methadone," American Academy of Hospice and Palliative Medicine National Conference, June 2001).

Considerable controversy has arisen regarding conversion ratios for methadone. Recently experts have noted a useful principle: the higher the dosage of the opioid being converted to methadone, the lower the conversion methadone dose should be.30,31 As summarized by Ripamonti, "The results of our study confirm that methadone is a potent opioid, more potent than believed. Caution is recommended when switching from any opioid to methadone, especially in patients who are tolerant to high doses of opioids."31

Palliative Care Note
Do not increase the dose of methadone any more rapidly than every three days in order to avoid the risk of dose-stacking.

Fentanyl Patches

Fentanyl patches may be useful for patients with chronic, stable pain who cannot use the oral route for opioid administration. Patches should not be used for acute pain or in very unstable situations (rapidly escalating or deescalating pain). Fentanyl has a very short half-life. Transcutaneous patches allow a noninvasive, nonenteral route of opioid delivery, which can be very useful. Serum blood levels remain stable, allowing consistent analgesia and minimizing side effects. Fentanyl patches are expensive. The lowest-dose patch, 25 micrograms per hour, changed every 72 hours, is too strong for some milder chronic pain syndromes. The patches work poorly on very hairy or oily skin. Some patients become allergic to the patches. Absorption increases with increased skin temperature, as with fever, which can be a problem for patients with temperature spikes.32 Additionally, there are anecdotal reports of decreased absorption (and analgesia) with hypothermia, as is commonly present in the dying process. The clinical significance of these temperature effects is debatable. Further research is needed. Although the drug has a short half-life, it takes approximately 12 to 16 hours to build a reservoir of the drug in the subcutaneous fat when initiating therapy and somewhat longer for the drug to wear off when discontinuing the patch. Caution should be exercised during initiation and discontinuation of therapy with this drug. On initiation care must be taken to ensure adequate analgesia until the patch "kicks in." If a long acting opioid, such as SR morphine, is given at the time the patch is placed, this is usually adequate, as this dose will last approximately 12 hours. Otherwise, short-acting agents, such as subcutaneous injections, must be given. Patches cannot be cut in half to reduce the dosage.

Tramadol

Recently available tramadol is an opioidlike drug that binds mu receptors, as do opioids. This drug is unique in that it also blocks reuptake of serotonin and norepinephrine in the CNS. Such reuptake inhibition is a coanalgesic effect to opioid receptor blockade. This inhibition is believed to be partially responsible for the analgesic properties of the drug. Initially, it was thought to have less potential for abuse and to cause fewer side effects. However, with more widespread use concerns have arisen as to abuse potential, and other common opioid side effects have been observed. This drug is more expensive than are traditional agents, and thus routine use is not encouraged. It may be considered in cases with special concerns regarding constipation or respiratory depression.33

Opioid Combinations

Combination medications, such as acetaminophen with codeine, oxycodone, or hydrocodone, are similar in terms of duration of action. They differ in terms of opioid potency and coanalgesic dose (acetaminophen or aspirin). Oxycodone (in Percocet, Percodan) appears roughly equipotent and similar in action to hydrocodone (in Vicodin), although good bioequivalent studies for hydrocodone have not been done. However, Vicodin contains 500 mg of acetaminophen, compared to 325 mg in Percocet. These medications are effective when a short-acting agent is needed for mild to moderate pain. Their use is limited by the addition of acetaminophen or aspirin, which are toxic in high doses. Acetaminophen and aspirin as antipyretics may also mask fevers in cases when it would be important to identify a fever, such as immunosuppressed states and postoperatively. Various formulations are available in both pill and elixir forms. Generic formulations, when available, are less expensive.

Acetaminophen with codeine is probably the most commonly used combination analgesic. Codeine is both a direct analgesic, weakly binding mu receptors, and a prodrug. It is converted into morphine in the liver. Patients deficient in a converting enzyme, CYP2D6 (10% of population) or those taking inhibitors of this enzyme, (examples are quinidine, cimetidine and fluoxetine), may not achieve analgesia because of an inability to convert codeine to morphine.34 Such patients may experience relief with other agents, such as acetaminophen with oxycodone.

Perhaps the biggest problem associated with these drugs is that many physicians will not prescribe stronger opioids when needed if the patient is receiving a maximum dosage of a combination drug. Whether this is out of ignorance, fear, or, at times, laziness is hard to say. I think of this barrier to better pain relief as "the combo wall." However, the barrier exists only in the mind of the prescribing physician. It is very easy to get over this wall - just use an opioid without acetaminophen. For example, if using oxycodone with acetaminophen, simply give pure oxycodone in either a long- or short-acting formulation and continue to titrate up the drug as needed. In the United States certain combo drugs such as hydrocodone and acetaminophen have a lower level of regulatory control. In some states, special prescriptions, triplicates, are required when prescribing a pure opioid. Although using triplicates, where necessary, is a nuisance, it seems inexcusable to deny patients pain relief if needed because of the hassle involved in filling out these forms.

Meperidine (Demerol)

Meperidine has few, if any, advantages over morphine. Meperidine is different in subtle ways from other opioids (greater smooth muscle relaxing effects related to anticholinergic effects, less anti-tussive effect), but these offer no definitive advantages. If given, meperidine should be given IM or IV, not SC, as it is irritating.9 Meperidine has a toxic metabolite, normeperidine, with a longer half-life than meperidine, which can cause altered mental status, myoclonus, and seizures. This is particularly true in the presence of decreased renal function. Meperidine should not be used for more than 72 hours, not for chronic pain, and never in the presence of renal failure.

Propoxyphene (Darvon, Darvocet)

I can think of no reason why propoxyphene-containing agents would be drugs of choice. The analgesia provided is not superior to that of other agents, and there may be a greater potential for side effects associated in part with the accumulation of norprorpoxyphene, a metabolite that can cause cardiac toxicity.35 The half-life of propoxyphene is 12 to 15 hours and is 30 to 36 hours for norpropoxyphene. Because of these prolonged half-lives, it takes two to three days to achieve steady state serum levels.9 Thus, there is a potential for dose-stacking, as with methadone.

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Palliative Care Perspectives

James L. Hallenbeck, M.D.

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Copyright 2003 by Oxford University Press, Inc.

The online version of this book is used with permission of the publisher and author on web sites affiliated with the Inter-Institutional Collaborating Network on End-of-life Care (IICN), sponsored by Growth House, Inc.