Page 1660 - Hematology_ Basic Principles and Practice ( PDFDrive )

1478 Part VIII Comprehensive Care of Patients with Hematologic Malignancies

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patient on morphine experiences persistent or debilitating nausea, the adjusted to reflect the rescue doses. When converting patients
rotation to another opioid at an equianalgesic dose should be con- directly from intravenous fentanyl to intravenous methadone, a
sidered (see box on Relative Potencies of Commonly Used Opioids). conversion ratio of 25 µg/hour of fentanyl to 0.1 mg/hour of metha-
Because of incomplete crosstolerance, the initial dose for patients done has been found in a pilot study to be a safe and effective initial
taking higher doses of opioids should be reduced by approximately infusion rate. 32
25%–50%. The short-acting rescue medication can provide relief if A relatively new opioid to the US market that is now available
this initial dose does not prove adequate. in both extended release and immediate release is oxymorphone.
Methadone is increasingly used for patients with moderate-to- Oxymorphone extended release has been found to provide safe
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severe pain. It is by far the least expensive of the opioids; can be and effective pain relief for cancer pain. Oxymorphone extended
given by the oral, sublingual, rectal, intravenous, and epidural routes; release is dosed twice daily and is about twice as potent as
and may have particular usefulness in patients with poor tolerance oxycodone. 34
to other opioids. Methadone has anecdotally been used for neuro- Levorphanol, which is chemically similar to dextromethorphan
pathic pain; however, recent clinical trials have not demonstrated (an NMDA antagonist and cough suppressant), is a potent opioid
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this benefit. Methadone is structurally unrelated to morphine and that may be considered for patients with severe cancer pain. It was
fentanyl, and can be used in the rare case of true allergy to these originally synthesized as an alternative to morphine more than 40
medications. It is also helpful when patients have neurotoxic side years ago. It has a greater potency than morphine, approximately five
effects of other opioids. Methadone is a potent µ-opioid receptor times as potent in its oral formulation. Analgesia is achieved through
agonist. The l-isomer has higher binding affinity for delta opioid its agonistic activity at µ-, δ-, and κ-opioid receptors, as well as by
receptors, which reduces tolerance, while the d-isomer has N-methyl- its antagonism of NMDA receptors. Levorphanol can be given orally,
D-aspartate (NMDA) receptor antagonism and 5-hydroxytryptamine intravenously, and subcutaneously.
and norepinephrine reuptake blockade, which may be helpful in Buprenorphine has long been used to treat patients with addiction
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providing analgesia. Patients with neuropathic pain and patients as an alternative to methadone. It is available buccal/sublingually,
taking opioids chronically have increased levels of NMDA recep- intravenously, and now as a transdermal patch. Buprenorphine has
tors in the dorsal horn of the spinal cord. NMDA antagonizes the been shown to be very effective in treating cancer pains (including
activity of the opiate receptors. Blocking the NMDA receptors neuropathic) and provides several important advantages over other
therefore enhances the analgesic effect of externally administered opioids: It is associated with less cardiotoxicity (does not significantly
opioids. Ketamine, a pure NMDA antagonist, similarly enhances prolong the QTc interval), respiratory depression, cognitive impair-
opioid efficacy but is associated with more cognitive side effects than ment, and constipation, and is one of the safer opioids to use in
methadone. elderly patients or patients with renal dysfunction. 35
Methadone interacts with inducers and inhibitors of the cyto- Meperidine is eight to 10 times less potent than morphine and
chrome P450 system. It is extensively metabolized by CYP1A2, has a short duration of action, approximately 2–3 hours. Normeperi-
CYP3A4, and CYP2D6; the first two are induced by a number of dine, an active metabolite which induces dysphoria, is excitatory to
drugs and other substances (e.g., cigarette smoke), and the last the CNS and can cause agitation, tremors, myoclonus, and seizures,
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enzyme has a genetic polymorphism. Drug levels of desipramine and especially in high doses, with prolonged use or in renal failure.
zidovudine increase when patients are receiving methadone. Drugs Normeperidine has a half-life of 13–24 hours, which can lengthen
that lower the levels of methadone include phenytoin (by 50%), with renal failure. The seizure incidence is further increased if the
phenobarbital, carbamazepine, rifampicin, and risperidone, each of opioid antagonist naloxone (Narcan) must be given. Therefore
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which has precipitated withdrawal symptoms. Drugs that raise the meperidine is not recommended for use in patients with long-lasting
serum methadone levels include ketoconazole, fluconazole, fluoxetine, moderate-to-severe pain. 1,7
and fluvoxamine. The selective serotonin reuptake inhibitors (SSRIs)
(except venlafaxine) may raise methadone levels in CYP2D6 rapid
metabolizers. Routes of Delivery
Methadone can cause prolongation of the QT interval. A mean
methadone dose of 400 mg/day (standard deviation: 283 mg) was Opioids can be delivered noninvasively (orally, rectally, transmuco-
found in 17 patients with torsades de pointes. In an evaluation of sally, or transdermally) or invasively (subcutaneously, intravenously,
reports of methadone-related adverse events to the US Food and or by spinal infusion). For patients switched from one route to
Drug Administration (FDA), approximately 1% of the greater than another such as oral or rectal to parenteral or spinal medication, or
5000 reports were of QT prolongation or torsades de pointes. The vice versa, the dose must be converted accordingly to avoid overdose
median dose was 345 mg with a range of 29–1680 mg. Drugs that or undertreatment (see box on Relative Potencies of Commonly Used
also prolong the QT interval, such as metoclopramide and olanzap- Opioids).
ine, should be used with caution in patients receiving significant
doses of methadone. Gabapentin, the drug used most often as a Oral Route
neuropathic pain adjuvant, does not interact with methadone Most patients can achieve excellent pain relief with short-acting and/
metabolism. There is insufficient evidence to recommend a screening or sustained-release oral opioid preparations. The typical onset of
interval or dose threshold for detecting methadone-induced QTc short-acting opioids via the oral route is 45 minutes to 1 hour, with
prolongation. 31 a typical duration of action around 3–4 hours. When tablets and
Other difficulties with using methadone lie in its variable and long capsules are not feasible, many liquid forms are available in various
biologic half-life, and the controversy about its equianalgesic dosing concentrations. Some solutions do contain alcohol, which can be
range. Some studies have reported that the equianalgesic dose of irritating to patients with oral lesions.
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morphine to methadone varies as the dose of morphine increases.
Dose ratios vary from 4 : 1 at morphine doses of 30–90 mg, to 6 : 1 Rectal Route
at 90–300 mg, and to 8 : 1 at doses of more than 300 mg of mor- Rectal opioids (i.e., morphine, oxymorphone, and hydromorphone)
phine. Other studies report a ratio of 20 : 1 for doses of oral morphine replace subcutaneous injections in patients who are suddenly unable
equivalents greater than 1000 mg. Some physicians advise a 3-day to take oral medications. They have about the same potency and
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conversion to methadone. On the first day, the dose of the old opioid half-life as orally administered agents and must therefore be admin-
is reduced by one-third, and one-third of the calculated dose of istered frequently. Oxycodone has been shown to have a similar mean
methadone is given; the second day, the dose of the remaining opioid bioavailability but with a large interpatient variability but longer
is reduced by half, and the dose of methadone is only increased if the duration of activity (8 hours). Although not approved by the FDA,
patient is experiencing moderate-to-severe pain; the third day, the old in single-dose bioavailability studies of sustained-release morphine
opioid is discontinued, and the standing dose of methadone is preparations, despite delayed absorption from the rectal route, total