Opioid Analgesics
Opioids are the primary analgesics used in the management of moderate to
severe pain. Opioid binding to specific receptors within and outside the
CNS produces analgesia. Opioid analgesics are categorized as agonist,
partial agonists or mixed agonist-antagonists depending upon binding
affinity, specific receptor binding and activity at the specific receptor
(See Tables VII and VIII).
Opioid Agonists
1. Morphine sulfate (immediate release) a strong, short-acting (3-4 hours)
opiate agonist. It is the drug of choice for severe cancer pain occurring
at any stage of a patient's disease. Morphine should not be reserved only
for terminal care; it is safe to use over prolonged periods if necessary.
The preferred route of administration is oral. Orally administered
morphine provides pain relief comparable to that of parenterally
administered morphine which can be achieved if one remembers the 3:1
oral-to-parenteral ratio for dosing. The oral dose must be three times the
parenteral one because the oral dose is subject to the "first pass" effect
in the liver. The "larger" oral dose is illusory because of the phenomenon
of biotransformation explained earlier. The same dose ultimately reaches
the opiate-binding sites in the central nervous system with either the
oral or parenteral route. (See Table III - Method for Converting Other
Narcotics to Equianalgesic Dose of Morphine, pages___.)
Controlled-release morphine- Morphine is now available in tablets that
release the drug over 8-24 hours. This obviates taking the immediate
release form every 3-4 hours. There are two major advantages to this long
duration. Probably most important, the patient is allowed to sleep for
longer periods uninterrupted by pain or by waking up to take pain
medication. Regular or immediate-release morphine should always be ordered
concomitantly on a p.r.n. basis (one of the rare, justifiable occasions to
use p.r.n. orders) with controlled-release morphine to cover episodes of
"breakthrough" pain that might occur during the interval covered by the
controlled-release morphine. THESE TABLETS CANNOT BE CUT OR CRUSHED OR
ALTERED IN ANY WAY WITHOUT DESTROYING THE LONG-ACTING FEATURE OF THEM.
2. Hydromorphone hydrochloride (Dilaudid Hydrochloride) - a strong,
short-acting (3-4 hours) opioid agonist. As with morphine, the oral route
is preferable. The oral-to-parenteral dose ratio is 5:1.
3. Methadone (Dolophine) a strong opioid agonist with analgesic activity
for 4-6 hours following a single dose. This longer duration of action is
related to its long plasma half life. The plasma half life varies between
13-36 hours, and although the analgesic activity does not last that long,
the drug accumulates in the blood with repeated dosing, producing
excessive sedation if the dose is not properly adjusted. Because of its
long plasma half life, adequate pain relief may be difficult to achieve
initially with methadone alone and rapid dose adjustments are more
difficult. The-oral to-parenteral dose ratio is 2:1.
4. Levorphanol tartrate (Levo-Dromoran) - a strong opioid agonist with
analgesic activity for 4-6 hours. Its prolonged analgesic activity is due
to its long half life (though not as long as that of methadone) and
lipophilic character. Its activity is similar to methadone's. The
oral-to-parenteral dose ratio is 2:1.
5. Fentanyl is a strong very short-acting (1 hour) opioid agonist. Given
the short duration of action, continuous pain requires continuous
administration. In addition to parenteral and intraspinal formulations,
fentanyl is also available in a transdermal delivery system (Duragesic©).
(colloquially referred to as łthe patch.˛) Fentanyl doses above 25 ug/hr
should not be used in opioid-naive patients. Transmucosal fentanyl is
available for procedure related pain and pre-anesthetic induction in
children. A lozenge impregnated with fentanyl attached to a stick is
available for the treatment of breakthrough pain. This can be used in
conjunction with the Duragesic system. It is usually desirable to
establish pain control with immediate release morphine and then switch to
the transdermal system for convenience. Standard equianalgesic dosing
conversion tables report that morphine 10 mg IV is equipotent to fentanyl
100 ug IV. (For specific information pertaining to clinical use
Duragesic©, see Table II - Severe Pain: Strong Opioids, Page__.
6. Meperidine hydrochloride (Demerol Hydrochloride) - a strong, very
short-acting (2-3 hours) opioid agonist. It is not recommended for
treatment of chronic pain because it has a short duration of action and
because repeated doses may cause central nervous system (CNS) toxicity
(tremors, confusion, and/or seizures) as a result of accumulation of the
metabolite normeperidine, which has a longer plasma half life than the
parent meperidine. This accumulation is especially a problem in patients
with impaired renal function and in those receiving large parenteral
doses. The oral-to-parenteral dose ratio is 4:1.
7. Oxymorphone hydrochloride (Numorphan Hydrochloride) - a strong,
short-acting (3-4 hours) opioid agonist with characteristics similar to
those of morphine.
8. Oxycodone hydrochloride - a strong, short-acting (3-4 hours) opioid
agonist. It is commonly combined with aspirin or acetaminophen. Oxycodone
is available only for oral administration in both tablet and liquid form.
When used in combination care should be taken to avoid toxic doses of the
non-opioid
Oxycodone controlled release (Oxycontin©) is available in tablets
releasing oxycodone over an 8-12 hour period. See Morphine controlled
release above. AS WITH CONTROLLED RELEASE MORPHINE TABLETS, OXYCONTIN
TABLETS CANNOT BE CRUSHED, DIVIDED, OR ALTERED IN ANY WAY WITHOUT
DESTROYING THE CONTROLLED RELEASE FEATURE OF THEM.
9. Hydrocodone bitartrate (Vicodin, Lortab) is a moderately strong,
short-acting (3-4 hours) opioid agonist. The hydrocodone to morphine po
conversion ratio is not well established, but thought to be approximately
1.0: 0.15. Plain hydrocodone is not available; all preparations are
combined with APAP, ASA or NSAID. Calculation of the total daily dose of
APAP, ASA or NSAID administered in combination with hydrocodone is
critical to assure that the maximum daily dose is not exceeded. For
example, several combinations contain 750 mgs of APAP per tablet.
Administration of 8 daily tablets containing APAP 750 mg reaches the
maximum daily APAP dose range of 4-6g/24 hours. Frequent dosing (e.g., 2
tabs q 2 hrs) will provide a toxic dose of 18 grams of APAP. If the
maximal dose of ASA or APAP is exceeded in order to provide adequate
opioid, change to more potent opioid agonist. The ASA and APAP can be
continued as single agents within the recommended dosing range.
10. Codeine is a weak, short-acting (3-4 hours) opioid agonist. The
codeine to morphine po conversion ratio is approximately 1.0:0.15. Codeine
is available as a single agent although the typical oral formulation
administered is in combination with ASA or APAP. Prescribers are
cautioned to be aware of the total daily dose of APAP or ASA. The
oral-to-parenteral dose ratio is 2:1.
11. Propoxyphene hydrochloride (Darvon©) is a weak, short-acting (3-4
hours) opioid agonist. The propoxyphene to morphine po conversion ratio is
approximately 1.0:0.15. Propoxyphene is as available as a single agent or
in combination with ASA or APAP. Its metabolite, norpropoxyphene, can
accumulate with repeated dosing and result in CNS toxicity.
Mixed agonist-antagonists
Mixed opioid agonist-antagonists medications have predominantly agonist
action but also clinically significant opioid antagonist activity.
Pentazocine, nalbuphine and butorphanolare mixed agonists-antagonists.
They are available in the following formations: butorphanol-parenteral and
inhalant, pentazocine-parenteral and oral, nalbuphine-parenteral. When
mixed opioid agonist-antagonist are administered to individuals
concurrently receiving an opioid agonist, an opioid agonist withdrawal
reaction may be precipitated similar to the withdrawal phenomenon induced
by naloxone hydrochloride (Narcan©). Consequently, pain will increase.
Mixed opioid agonist-antagonists should never be given simultaneously with
a pure opioid agonist nor should they be altered with opioid agonists
(e.g., morphine alternated with pentazocine hydrochloride [Talwin©]).
Furthermore, mixed opioid agonist-antagonists have a high incidence of
unpleasant psychomimetic effects. Because of these characteristics, mixed
opioid agonist-antagonists are not recommended for treatment of chronic
pain. Their most common use is for post-operative pain in individuals who
are opioid agonist naive. Post-operative administration of a mixed
agonists-antagonists to an individual taking opioid agonist preoperatively
will precipitate withdrawal.
Partial Opioid Agonist
Buprenorphine (Buprenex©) is a partial agonist available in a parenteral
formation. It binds with opioid receptor sites less tightly than pure
agonists, producing less effect than pure agonist. Buprenorphine has a
ceiling effect to analgesia. Concomitant use with an opioid agonists may
precipitate opioid withdrawal syndrome. Like mixed opioid
agonist-antagonist, there is a propensity to develop psychomimetic effects
with prolonged or high dose therapy. Partial agonist are not recommended
for the treatment of cancer pain.
Other Categories of Drugs with Analgesic Properties
Recent research has shown that several categories of drugs that are not
traditional analgesic drugs have analgesic effects. This is especially
true when these drugs are administered intrathecally. One such drug is
clonidine hydrochloride, an alpha-adrenergic agonist which acts primarily
in the CNS causing inhibition of sympathetic vasomotor centers. Its
primary indication is for the treatment of hypertension. This drug has
recently been approved by the Food and Drug Administration for the
treatment of severe pain in cancer patients in combination with opioids
whose pain is not adequately relieved by opioids alone. It is more likely
to be effective in neuropathic pain than somatic or visceral pain.
Patients selected for treatment with this drug must be done very carefully
and its use requires highly trained experts in this type of pain
management. It is mentioned here to alert health care professionals who
are dealing with patients whose pain management is extremely difficult
that such options exist, but only in centers that deal with such difficult
pain problems. It is marketed under the trade name of Duraclon.
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