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Opioid analgesics can be classified as pure agonists or agonist-antagonists,
based on their interactions with opioid receptors. There have been very
few comparative trials and the selection of opioids for different clinical
settings is typically based on clinical judgment, familiarity with the drug,
cost, and trial-and-error (Table).
The agonist-antagonist drugs include a mixed agonist-antagonist subclass--including
butorphanol, nalbuphine, pentazocine, and dezocine--and a partial agonist
subclass (including buprenorphine). Drugs in the mixed agonist-antagonist
subclass generally are not used for chronic pain because they have a ceiling
effect for analgesia, can reverse the effects of pure agonists in physically
dependent patients, and are available in short-acting formulations only.
Buprenorphine is now available as a sublingual formulation (marketed in
the United States for the treatment of addiction but able to be prescribed
“off-label” for pain) and a buprenorphine transdermal system
is now in development. Although this drug also has a ceiling effect and
also can potentially cause withdrawal in patients who are physically dependent
on a pure agonist, it is long-acting and may become a useful drug in the
long-term management of moderate to severe pain in those who have limited
prior opioid exposure.
In the United States, the short-acting pure agonist opioids used “as
needed” for moderate to severe pain include combination products containing
codeine, hydrocodone, dihydrocodeine, or oxycodone combined with acetaminophen,
aspirin, or ibuprofen, and a group of single-entity pure agonists such as
morphine (Table). The unique analgesic, tramadol, which acts through both
an opioid (mu agonist) and a nonopioid (serotonergic and noradrenergic)
mechanism, also is available. Meperidine also is occasionally used but is
not preferred for chronic pain management because of the potential for adverse
effects related to accumulation of an active metabolite, normeperidine.
These adverse effects include dysphoria, tremulousness, hyperreflexia, and
seizures.
The single-entity pure agonist opioids are conventionally used for severe
pain. In long-acting formulations, these drugs are prescribed in a fixed
schedule dose for chronic pain. They include morphine, hydromorphone, fentanyl,
and oxycodone. Oxymorphone is in development and will likely become available.
These drugs are also used in their immediate-release formulations for acute
pain, for initiating therapy in the opioid-naïve patient who is likely
to be transitioned to fixed scheduled dosing, and for providing “rescue
dose” for breakthrough pain during treatment with the long-acting
formulation. Levorphanol and methadone are longer half-life drugs generally
used in fixed scheduled dosing for chronic pain. There is very substantial
individual variation in the response of an individual to different opioids.
Both the overall balance between analgesia and side effects, and the pattern
of side effects, vary from opioid to opioid.
Table: Considerations in the Selection of A Specific Opioid for
Pain Management (.pdf)
Morphine has active metabolites. Morphine 6-glucuronide is an opioid that
may contribute to the analgesia and side effects observed during morphine
therapy. Morphine 3-glucuronide is a nonopioid that may cause toxicity,
possibly including myoclonus and worsening pain. Both metabolites accumulate
in patients with renal insufficiency. Patients who develop morphine toxicity,
particularly in the setting of renal insufficiency, should be offered a
trial of an alternative opioid, such as hydromorphone or fentanyl, in the
hope that lesser metabolite accumulation may contribute to a better response.
Methadone presents additional issues in drug selection. Because its half-life
can vary from 12 hours to more than 120 hours, the time to approach steady
state after treatment begins or is changed can be as brief as several days
or as long as 2 weeks. If the dose is rapidly increased to an effective
level, the plasma concentration can continue to rise toward steady-state
levels, and late toxicity can occur. For this reason, careful monitoring
for a prolonged period is needed after dosing is initiated or increased.
In most countries, methadone is available as a racemic mixture of the d-
and l- isomers. The d-isomer is not an opioid, but rather, is a NMDA receptor
antagonist. Because antagonism at the NMDA receptor produces analgesia independent
of opioid analgesia and also reverses opioid tolerance, this pharmacology
has been used to explain the observation that methadone may have a much
greater potency than anticipated, particularly when it is given to a patient
who already has been taking another opioid agonist. For this reason, a switch
to methadone from another drug should be accompanied by a reduction in the
calculated equianalgesic dose of 50-75%. Finally, it should be recognized
that there are new observations suggesting that methadone can prolong the
QTc interval; the clinical implications of this effect have not be clarified
yet. A trial of methadone usually is considered for patients whose opioid
requirements are increasing and side effects, such as sedation, confusion,
or myoclonus, are compromising therapy. Methadone is substantially less
expensive than other opioids and may also be useful if the cost of therapy
is an important consideration.
In the United States, clinicians who prescribe methadone or buprenorphine
for analgesic purposes must be clear about the differences between this
use and the use of these drugs to treat opioid addiction. Any clinician
can prescribe methadone or buprenorphine for pain. However, a special license
is required to use these drugs in the maintenance therapy for addiction.
References
Hanks GWC, Cherny N, Fallon M. Opioid analgesic therapy. In: Doyle D, Hanks
GWC, Cherny NI, Calman K, eds. Oxford Textbook of Palliative Medicine, Third
Ed. Oxford: Oxford University Press, 2004, pp 316-341. |
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