sobre ventas totales
4.5.4.1.10 Información a brindar para la presentación de un proyecto La información a brindar por parte de quienes presenten proyectos de
Drug Oral Parenteral Oral Parenteral Oral Parenteral Potential
Advantages Potential
Disadvantages Opioid Agonists2
Buprenorphine transdermal
Not available Not available Not available orally.
Transdermal doses available: 5, 10, and 20 mcg/h. Initiate 5 mcg/h patch for opioid-naïve patients (may currently be using nonopioid analge-sics); $84.03/
10 mcg/h
Not available Not available Not available 7-day analgesia; may be initiated in opioid-naïve patients.
Can titrate up dose after 72 hours.
QT prolongation.
Fentanyl Not available 100 mcg
every hour Not available 50–100 mcg IV/IM every hour or 0.5–1.5 mcg/kg/h IV infusion
$0.53/100 mcg
Not available 0.5–1 mcg/kg IV every 1–4 hours or 1–2 mcg/kg IV × 1, then 0.5–1 mcg/kg/h infusion
Possibly less neuroexcitatory effects, including in kidney failure.
Fentanyl oral transmucosal (Actiq); buccal (Fentora)
Not available Not available 200 mcg transmuco-sal; 100 mcg buccal; $18.80/
200 mcg transmu-cosal; $55.80/
200 mcg buccal
Not available Not available Not available For pain breaking through long- acting opioid medication.
Transmucosal and buccal formulations are not bioequiva-lent; there is higher bioavailability in buccal formulation.
PALLIATIVE CARE & PAIN MANAGEMENT
77 CMD T 2016
oral morphine:2 morphine 60–134 mg/d
orally = fentanyl 25 mcg/h patch; mor-phine 135–224 mg/d orally = fentanyl 50 mcg/h patch; mor-phine 225–314 mg/d orally = fentanyl 75 mcg/h patch; and morphine 315–
404 mg/d orally = fen-tanyl 100 mcg/h patch
$16.65/25 mcg/h dose is 25 mcg/h
patch in patients who have been tak-ing stable dose of opioids for at least 1 week at the equivalent of at least 60 mg/d of oral morphine.
Hydrocodone, extended release (Zohydro ER)
20 mg1 Not available 10 mg every 12 hours
$7.37/10 mg Not available Not available Not available Available as an extended-release formulation with-out acetaminophen Hydromorphone3
(Dilaudid) 7.5 mg every 3–4 hours 1.5 mg every
3–4 hours 1–2 mg every 3–4
hours; $0.45/2 mg 1.5 mg every 3–4 hours; $1.34/
2 mg
0.06 mg/every
3–4 hours 0.015 mg/kg every
3–4 hours Similar to morphine.
Available in inject-able high-potency preparation, rectal suppository.
Short duration.
Hydromorphone extended release (Exalgo)
45–60 mg every
24 hours Not available 8 mg every 24 hours;
15.21/8 mg Not available Not available Not available Similar to morphine Taper dose 25–50%
every 2–3 days to 8 mg/d to discontinue.
Levorphanol
(Levo-Dromoran) 4 mg every 6–8 hours 2 mg every
6–8 hours 4 mg every 6–8 hours;
$2.14/2 mg Not available 0.04 mg/kg every
6–8 hours Not available Longer-acting than morphine sulfate.
Meperidine4 (Demerol)
300 mg every 2–3 hours; usual dose 50–150 mg every 3–4 hours
100 mg every 3 hours
Not recommended 100 mg every 3 hours; $3.23/
100 mg
Not
recommended
0.75 mg/kg every 2–3 hours
Use only when single dose, short-dura-tion analgesia is needed, as for out-patient procedures like colonoscopy.
Not recommended for chronic pain or for repeated dosing.
Short duration.
Normeperidine metabolite accumu-lates in kidney failure and other situations, and in high concen-trations may cause irritability and seizures.
(continued)
ChAPTER 5
CMD T 2016
(compared to morphine 30 mg orally
or 10 mg IV/SC)1 Adults ≥ 50 kg Body Weight Adults < 50 kg Body Weight
Drug Oral Parenteral Oral Parenteral Oral Parenteral Potential
Advantages Potential
Disadvantages Methadone
(Dolophine, others)
10–20 mg every 6–8 hours (when convert-ing from < 100 mg long-term daily oral morphine5)
5–10 mg every 6–8 hours
5–20 mg every 6–8 hours; $0.44/10 mg
2.5–10 mg every 6–8 hours; $12.37/
10 mg
0.2 mg/kg every 6–8 hours
0.1 mg/kg every 6–8 hours
Somewhat longer acting than mor-phine. Useful in cases of intolerance to morphine.
May be particularly useful for neuro-pathic pain.
Available in liquid formulation.
Analgesic duration shorter than plasma duration. May accu-mulate, requiring close monitoring during first weeks of treatment.
Equianalgesic ratios vary with opioid dose. Risk of QT prolongation at doses >100–
150 mg/d. Baseline ECG recommended.
Morphine3 immedi-ate release (Morphine sul-fate tablets, Roxanol liquid)
30 mg every 3–4 hours (around-the-clock dosing); 60 mg every 3–4 hours (single or intermittent dosing)
10 mg every
3–4 hours 4–8 mg every 3–4 hours; used for breakthrough pain in patients already taking controlled-release prepara-tions; $0.27/15 mg tab; 0.48/20 mg liquid
10 mg every 3–4 hours; $1.96/
10 mg
0.3 mg/kg every
3–4 hours 0.1 mg/kg every
3–4 hours Standard of compari-son; multiple dos-age forms available.
No unique problems when compared with other opioids.
Active metabolite accumulates in renal insufficiency.
Morphine controlled release3 (MS Contin, Oramorph)
90–120 mg every
12 hours Not available 15–60 mg every 12
hours; $3.17/30 mg Not available Not available Not available
Morphine extended release (Kadian, Avinza)
180–240 mg every 24 hours
Not available 20–30 mg every 24 hours; $5.69/30 mg
Not available Not available Not available Once-daily dosing possible.
Oxycodone (Roxicodone, OxyIR)
20–30 mg every
3–4 hours Not available 5–10 mg every 3–4
hours; $0.48/5 mg Not available 0.2 mg/kg every
3–4 hours Not available Similar to morphine.
PALLIATIVE CARE & PAIN MANAGEMENT
79 CMD T 2016
tion or intranasal administration).
Oxymorphone6 oral, immediate release (Opana)
10 mg every 6 hours Not available 5–10 mg every 6
hours; $3.24/5 mg Not available Taking with food can
increase serum levels by 50%.
Equianalgesic dosing conversion range is wide.
Oxymorphone6 extended release (Opana ER)
30–40 mg every
12 hours Not available 15–30 mg every 12
hours; $3.34/10 mg Not available Taking with food can
increase serum levels by 50%.
Equianalgesic dosing conversion range is wide.
Combination Opioid–Nonopioid Preparations Codeine7,8 (with
aspirin or acetaminophen)9
180–200 mg every 3–4 hours; commonly available dose in combination with acetaminophen, 15–60 mg of codeine every 4–6 hours
130 mg every
3–4 hours 60 mg every 4–6
hours; $0.54/60 mg 60 mg every 2 hours (IM/SC); price not available in the United States
0.5–1 mg/kg
every 3–4 hours Not recommended Similar to morphine. Closely monitor for efficacy as patients vary in their ability to convert the pro-drug codeine to morphine.
Hydrocodone6 (in Lorcet, Lortab, Vicodin, others)9
30 mg every 3–4 hours Not available 10 mg every 3–4
hours; $0.59/5 mg Not available 0.2 mg/kg every
3–4 hours Not available Combination with
acetaminophen limits dosage titration.
Oxycodone7 (in Percocet, Percodan, Tylox, others)9
30 mg every 3–4 hours Not available 10 mg every 3–4
hours; $1.04/5 mg Not available 0.2 mg/kg every
3–4 hours Not available Similar to morphine. Combination with acetaminophen and aspirin limits dosage titration.
Opioid Agonists, Norepinephrine Reuptake Inhibitors Tapentadol
(Nucynta) Not known Not known Start 50–100 mg
once, may repeat dose in 1 hour.
Can increase to 50–100 mg every 4 hours. Maximum daily dose 600 mg ;
$5.17/100 mg
Not available Not available Avoid in severe renal
or hepatic impairment.
(continued)
ChAPTER 5
CMD T 2016
(compared to morphine 30 mg orally
or 10 mg IV/SC)1 Adults ≥ 50 kg Body Weight Adults < 50 kg Body Weight
Drug Oral Parenteral Oral Parenteral Oral Parenteral Potential
Advantages Potential
Disadvantages Tapentadol,
extended release (Nucynta ER)
Not known Not known Start 50 mg orally every 12 hours. Can increase by 50-mg increments twice daily every 3 days to dose of 100–250 mg twice daily ;
$6.61/100 mg
Not available Not available Avoid in severe renal
or hepatic impairment.
Tramadol
(Ultram) Not known Not known Start 25 mg orally
daily. Can increase by 25 mg every 3 days to 25 mg orally 4 times daily, then may increase by 50 mg/day every 3 days to 100 mg orally 4 times daily. Limit of 300 mg/day in patients > 75 years old; $0.80/50 mg
Not available Not available If creatinine clearance
less than 30, limit to 200 mg/day; with cirrhosis, limit to 100 mg/day.
1Published tables vary in the suggested doses that are equianalgesic to morphine. Clinical response is the criterion that must be applied for each patient; titration to clinical efficacy is necessary.
Because there is not complete cross-tolerance among these drugs, it is usually necessary to use a lower than equianalgesic dose initially when changing drugs and to retitrate to response.
2Conversion is conservative; therefore, do not use these equianalgesic doses for converting back from fentanyl patch to other opioids because they may lead to inadvertent overdose. Patients may require breakthrough doses of short-acting opioids during conversion to transdermal fentanyl.
3Caution: For morphine, hydromorphone, and oxymorphone, rectal administration is an alternative route for patients unable to take oral medications. Equianalgesic doses may differ from oral and parenteral doses. A short-acting opioid should normally be used for initial therapy.
4Not recommended for chronic pain. Doses listed are for brief therapy of acute pain only. Switch to another opioid for long-term therapy.
5Methadone conversion varies depending on the equivalent total daily dose of morphine. Consult with a pain management or palliative care expert for conversion.
6Caution: Recommended doses do not apply for adult patients with kidney or liver impairment or other conditions affecting drug metabolism.
7Caution: Doses of aspirin and acetaminophen in combination products must also be adjusted to the patient’s body weight.
8Caution: Doses of codeine above 60 mg often are not appropriate because of diminishing incremental analgesia with increasing doses but continually increasing nausea, constipation, and other side effects.
9Caution: Monitor total acetaminophen dose carefully, including any OTC use. Total acetaminophen dose maximum 3 g/d. If liver impairment or heavy alcohol use, maximum is 2 g/d. Available dosing formulations of these combination medications are being adjusted to reflect increased caution about acetaminophen toxicity. Acetaminophen doses in a single combination tablet or capsule will be limited to no more than 325 mg.
Note: Average wholesale price (AWP, generic when available) for quantity listed. Source: Red Book Online, 2015, Truven Health Analytics, Inc. AWP may not accurately represent the actual pharmacy cost because wide contractual variations exist among institutions. Data from Jacox AK et al. Management of Cancer Pain: Quick Reference Guide for Clinicians No. 9. AHCPR Publication No. 94–0593. Rockville, MD. Agency for Health Care Policy and Research, Public Health Service, U.S. Department of Health and Human Services. March 1994, and from Erstad BL. A rational approach to the management of acute pain states. Hosp Formul 1994;29 (8 Part 2):586.
For chronic stable pain, long-acting medications are preferred, such as oral sustained-release morphine (one to three times a day), oxycodone (two or three times a day), hydrocodone (two times a day), or methadone (three or four times a day) (Table 5–3). Clinicians prescribing opi-oids must understand the concept of equianalgesic dosing (Table 5–3). The dosages of any full opioid agonists used to control pain can be converted into an equivalent dose of any other opioid. This approach is helpful in estimating the appropriate dose of a long-acting opioid based on the amount of short-acting opioid required over the preceding days. For example, 24-hour opioid requirements estab-lished using short-acting opioid medications can be con-verted into equivalent dosages of long-acting medications or formulations. Cross-tolerance is often incomplete, how-ever, so generally only two-thirds to three-quarters of the full, calculated equianalgesic dosage is administered ini-tially when switching between opioid formulations.
Methadone deserves special consideration among the long-acting opioids because it is inexpensive, available in a liquid formulation, and may have added efficacy for neuro-pathic pain. However, equianalgesic dosing is complex because it varies with the patient’s opioid dose, and caution must be used at higher methadone doses (generally more than 100–150 mg/day) because of the risk of QT prolonga-tion. Baseline ECG is recommended before starting metha-done except at the very end of life where comfort is the only goal. Given the complexities of management and the increasing prevalence of methadone overdose in the United States (see below), consultation with a palliative medicine or pain specialist may be appropriate.
Transdermal fentanyl is appropriate for patients already tolerant to other opioids for at least 1 week at a dose equivalent to at least 60 mg/day of oral morphine (equivalent to transdermal fentanyl 25 mcg/h every 72 hours) and there-fore should not be used in the postoperative setting or be the first opioid used. Medications that inhibit cytochrome P450 3A4, such as ritonavir, ketoconazole, itraconazole, troleando-mycin, clarithrotroleando-mycin, nelfinavir, nefazodone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, flucon-azole, fosamprenavir, and verapamil, and grapefruit juice can cause increased levels and duration of transder-mal fentanyl. Since transdertransder-mal fentanyl can require 24–48 hours to achieve pharmacologic “steady state,”
patients should be weaned off their current opioid and given short-acting opioids while awaiting the full analgesic effect of transdermal fentanyl, and changes in dose of trans-dermal fentanyl should be made no more frequently than every 6 days.
While some clinicians and patients inexperienced with the management of severe pain may feel more comfortable with combined nonopioid-opioid agents, full agonist opi-oids are typically a better choice in patients with severe pain because the dose of opioid is not limited by the toxici-ties of the acetaminophen, aspirin, or NSAID component of combination preparations. There is no maximal allow-able or effective dose for full opioid agonists. The dose should be increased to whatever is necessary to relieve pain, remembering that not all pain is opioid sensitive and that certain types of pain, such as neuropathic pain, may
respond better to agents other than opioids, or to combina-tions of opioids with co-analgesics (see below).
While physiologic tolerance is possible with opioids, failure of a previously effective opioid dose to adequately relieve pain is usually due to worsening of the underly-ing condition causunderly-ing pain, such as tumor growth or new metastasis in a patient with cancer. In this case, for moder-ate unrelieved pain, the dose of opioid can be increased by 25–50%. For severe unrelieved pain, a dose increase of 50–100% may be appropriate. The frequency of dosing should be adjusted so that pain control is continuous.
Long-term dosing may then be adjusted by adding the average daily amount of short-acting opioid necessary for breakthrough pain over the preceding 72–96 hours to the long-acting medication dose. In establishing or reestablish-ing adequate dosreestablish-ing, frequent reassessment of the patient’s pain and medication side effects is necessary.
B. Opioid Adverse Effects
As opioids are titrated upward, increasing difficulty with the side effects can be expected. Constipation is common at any dose of opioid, and tolerance to this side effect does not develop over time. Opioid-induced constipation should be anticipated and prevented in all patients (see below).
Sedation can be expected with opioids, although toler-ance to this effect and to side effects other than constipa-tion typically develops within 24–72 hours at a stable dose.
Sedation typically appears well before significant respira-tory depression. If treatment for sedation is desired, dex-troamphetamine (2.5–7.5 mg orally at 8 AM and noon) or methylphenidate (2.5–10 mg orally at 8 AM and noon) may be helpful. Caffeinated beverages can also ameliorate minor opioid sedation.
Opioid-induced neurotoxicity—including myoclonus, hyperalgesia, delirium with hallucinosis, and seizures—
may develop in patients who take high doses of opioids for a prolonged period. Opioid-induced hyperalgesia appears to be a result of changes in both the peripheral and central nervous systems leading to sensitivity to pain. Typically benign or even soothing stimuli (eg, light massage) may be perceived as painful, and increasing opioid dose may exac-erbate the problem. These symptoms may resolve after lowering the dose or switching opioids (“opioid rotation”), especially to ones like fentanyl or methadone that do not have active metabolites. While waiting for the level of the offending opioid to fall, low doses of lorazepam, baclofen, or gabapentin may be helpful for treating myoclonus; halo-peridol may be useful for treating delirium. Avoiding or correcting dehydration may be helpful for prevention and treatment of opioid-induced neurotoxicity.
Nausea due to opioids may occur with initiation of therapy and resolve after a few days. Notably, unrelieved constipation may be a more likely cause of nausea in the setting of opioid use than opioid-induced nausea. Severe or persistent nausea despite treatment of constipation can be managed by switching opioids or by giving haloperidol, 0.5–4 mg orally, subcutaneously, or intravenously every 6 hours; prochlorperazine, 10 mg orally or intravenously or
are generally measured in terms of a reduction in the analog pain score of 2–3 points on a 10-point scale or in improve-ments in the important but less precise outcome of function.
Prior to considering a trial of daily opioids, clinicians should discuss these modest possible benefits with patients in order to help set realistic goals of therapy (eg, moving from an average pain of 7 to a 4). Clinicians should also set a deadline for reaching the patient’s goals. Since the published trials have generally lasted less than 16 weeks, it is reasonable to set a deadline before that, with some experts advocating a 90-day trial period. Limiting the time of a trial will also help prevent dose escalation to levels associated with increased risk of adverse effects, including overdose.
Many experts recommend developing a specific goal of improved function, and tracking the patient’s progress toward achieving this goal over time. But for the many patients who do not have specific, measurable goals—or who come to the clinician already on daily opioid medica-tion—monitoring response to treatment over time can be difficult. A useful tracking measure is asking about pain, energy, and general activity (PEG), which directs patients to quantify on a scale of 0–10 the following three outcomes: pain intensity on average over the last week;
how the pain has affected their energy level; and how much pain has impacted their general activity. Patients who do not progress toward their goal or whose PEG scores remain high over time may have pain that is unre-sponsive to opioids, and clinicians should reconsider the original diagnosis and use other modalities (both phar-macologic and nonpharphar-macologic) to provide analgesia.
Without a clear analgesic benefit from opioids for CNCP, the risks may predominate, and the ineffective therapy should be discontinued.
B. Risks of Long-Term Opioid Therapy
The risks of opioids are different from those of most other medications. One of the most attractive features of opioids is the absence of specific organ toxicity attendant to most other kinds of medications. However, not every patient with CNCP is a good candidate for long-term opioid therapy. In addition to the grave risks of addiction and death and the common side effects of sedation and constipation, long-term opioid use leads to increased risk of many problems, including hypogonadism, fracture, hyperalgesia, psychoso-cial problems, and fraught interactions with the health care team. When considering whether to initiate or continue opioids for CNCP, clinicians should delineate these specific risks for patients so an informed decision can be made.
In addition to overdose, the biggest concern of many patients and clinicians is addiction. The level of risk to the individual patient with CNCP is uncertain. While physical opioid dependence has been demonstrated with daily use in virtually all patients, the published risk of addiction in patients prescribed opioids for CNCP varies between less than 1% to more than 20%, with the lowest frequencies observed in studies that excluded patients with a history of substance abuse or addiction. Survey data found that nearly 80% of people in the United States who tried heroin for the first time in 2012 had already abused opioid medications.
25 mg rectally every 6 hours; or metoclopramide, 5–20 mg orally, subcutaneously, or intravenously before meals and bed. Ondansetron, 4–8 mg orally or intravenously every 6 hours, also relieves nausea but can contribute to constipa-tion. Most antiemetic treatments can contribute to sedaconstipa-tion.
Although clinicians may worry about respiratory depression with opioids, this side effect is uncommon when a low dose is given initially and titrated upward slowly. Patients at particular risk for respiratory depression include those with chronic obstructive pulmonary disease, obstructive sleep apnea, and baseline CO2 retention; those with liver or kidney or combined liver-kidney failure; and those with adrenal insufficiency or frank myxedema. Yet, even patients with severe pulmonary disease and obstructive
Although clinicians may worry about respiratory depression with opioids, this side effect is uncommon when a low dose is given initially and titrated upward slowly. Patients at particular risk for respiratory depression include those with chronic obstructive pulmonary disease, obstructive sleep apnea, and baseline CO2 retention; those with liver or kidney or combined liver-kidney failure; and those with adrenal insufficiency or frank myxedema. Yet, even patients with severe pulmonary disease and obstructive