DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Table 18–6
Guidelines for the Use of Opioids to Treat Chronic Pain
• Evaluation of the patient: A complete medical history and physical must be conducted and documented
in the medical record.
• Treatment plan: The treatment plan should state objectives that are used to determine treatment success.
• Informed consent and agreement: The physician should discuss the risks, benefits, and alternatives to chronic opioid therapy
with the patient. Many practitioners have developed an “opioid contract” that outlines the responsibilities of the physician
and the patient for continued prescription of controlled substances.
• Periodic review: At reasonable intervals, the patient should be seen by the physician to review the course of treatment and
document results of consultation, diagnostic, testing, laboratory results, and the success of treatment.
• Consultation: The physician should refer the patient for consultation when appropriate.
• Documentation/medical records: The physician should keep actual and complete medical records that include:
(a) medical history and physical examination; (b) diagnostic, therapeutic, and laboratory results; (c) evaluations and consultations;
(d) treatment objectives; (e) discussion of risks and benefits; (f) treatment; (g) medications including date, type,
dosage, and quantity prescribed; (h) instructions and agreements; and (i) periodic reviews.
• Compliance with controlled substances law and regulations: To prescribe, dispense or administer controlled substances,
the physician must be licensed in the state and comply with applicable state and federal regulations.
dressing changes (incident pain). These examples emphasize the
need for individualized management of increased or decreased pain
levels with baseline analgesic dosing supplemented with the use of
short-acting “rescue” medications as required. In the face of ongoing
severe pain, analgesics should be dosed in continuous or
“around-the-clock” fashion rather than on an as-needed basis. This
provides more consistent analgesic levels and avoids unnecessary
suffering (Vashi et al., 2005).
Opioid Tolerance. Chronic exposure to one opiate agonist typically
leads to a reduction in the efficacy of other opiate agonists. The
degree of tolerance can be remarkable. For example, 10 mg of an
oral opioid (such as morphine) is considered a high dose for a
treatment-naïve individual whereas 100 mg IV may produce only
minor sedation in severely tolerant individual.
Patient Physical State and Genetic Variables. Codeine,
hydrocodone, and oxycodone are weak analgesic prodrugs that are
Table 18–7
Oral Morphine to Methadone Conversion Guidelines
CONVERSION RATIOS
DAILY MORPHINE MORPHINE : METHADONE
DOSE(mg/24 h, ORALLY) (oral) (oral)
< 100 3 : 1
101-300 5 : 1
301-600 10 : 1
601-800 12 : 1
801-1000 15 : 1
> 1001 20 : 1
metabolized into the much more effective analgesic drugs morphine,
hydromorphone, and oxymorphone, respectively, by CYP2D6
(Supernaw, 2001). The analgesic properties of morphine, hydromorphone,
oxymorphone, propoxyphene, and fentanyl are largely due
to their direct influence on opioid receptors and do not require additional
metabolism, although the first metabolite of propoxyphene,
norpropoxyphene, is also an effective analgesic with a very long t 1/2
.
CYP2D6 activity is genetically diminished in 7% of whites, 3% of
blacks, and 1% of Asians (Eichelbaum and Gross, 1990); rendering
oxycodone, hydrocodone, and codeine relatively ineffective analgesics
in these “poor metabolizers” and potentially toxic for “ultrarapid”
metabolizers.
The activity of CYP2D6 is inhibited by selective serotonin
reuptake inhibitors, including fluoxetine, fluvoxamine, paroxetine,
sertraline, and bupropion, medications that are commonly administered
to pain patients. The CYP2D6 inhibition resulting from these
interacting medications may render opioids less effective as analgesics
in some patients. Whereas diminished activity of the CYP2D6
isoenzyme will lead to less efficacy of prodrug opioids, the opposite
occurs with methadone. Although methadone is primarily metabolized
through the CYP3A4 isoenzyme, genetic polymorphisms
involving deficiencies in the CYP2C9, CYP2CI9, and CYP2D6
isoenzymes may lead to surprisingly high methadone plasma concentrations
resulting in overdose.
Opioids are highly protein bound and factors such as plasma
pH may dramatically change binding. In addition, α 1
-acid glycoprotein
(AAG) is an acute-phase reactant protein that is elevated in cancer
patients and has a high affinity for basic drugs such as methadone
and meperidine. Morphine and meperidine should be avoided in
patients with renal impairment since morphine-6-glucuronide (a
metabolite of morphine) and normeperidine (a metabolite of meperidine)
are excreted by the kidney and will accumulate and lead to toxicity.
Other states that may increase the risk of adverse effects of the
opioids include chronic obstructive pulmonary disease, sleep apnea,
dementia, benign prostratic hypertrophy, unstable gait, and pretreatment
constipation.