Opioid
Dosage form
Strength
Starting doses of short-acting opioids for opioid naïve patients
Morphine
Oral solution
Tablets ER (q12 h)
Tablets ER (q 24 h)
Tablets IR
Injectable SC, IV, infusion
2, 4, 20 mg/mL
15, 30, 60, 100, 200 mg
Kadian: 10, 20, 30, 50, 60, 80, 100, 150, 200 mg
Avinza: 30, 45, 60, 75, 90, 120 mg
10, 15, 30 mg
Check hospital-specific concentrations
5–10 mg PO q 60 min as needed
2–3 mg IV q 30 min as needed
Methadone
Oral solution
Tablets
Injectable IV, infusion
1, 2, 10 mg/mL
5, 10 mg; 40 mg (dissolvable)
Check hospital-specific concentrations
NA
Fentanyl
Transmucosal (Buccal)
Transdermal
Injectable SC, IV, infusion
Actiq:200, 400, 600, 800, 1,200, 1,600 mg
Patches: 12 (delivers 12.5), 25, 50, 75, 100 mcg/h
Check hospital-specific concentrations
25–50 mcg IV q 30 min as needed
Hydromorphone
Oral solution
Tablets ER (q 24 h)
Tablets IR
Injectable SC, IV, infusion
1 mg/mL
8, 12, 24, 32 mg
2, 4, 8 mg
Check hospital-specific concentrations
2 mg PO q 60 min as needed
0.5 mg IV q 30 min as needed
Oxycodone
Oral solution
Tablets ER (q 12 h)
Tablets IR
1, 20 mg/mL
10, 15, 20, 30, 40, 60, 80 mg
5, 10, 15 mg
5 mg PO q 60 min as needed
Oxymorphone
Tablets ER (q 12 h)
Tablets IR
7.5, 10, 15, 20, 30, 40 mg
5, 10 mg
5 mg PO q 60 min as needed
Morphine remains the gold-standard opioid.
The benefits of morphine are:
It is relatively inexpensive and covered by most health plans.
It is available in a liquid formulation.
It is widely available.
It is well known.
Its familiarity translates to less medication errors compared with other opioids.
The liquid formulation is good for people who cannot swallow pills, have a feeding tube, or have poor bowel absorption, e.g., short bowel.
Morphine is metabolized by glucuronidation in the liver to morphine-6-glucuronide and morphine-3-glucuronide. Both metabolites are renally excreted and are known neurotoxins. Accumulation of the metabolites leads to opioid-induced neurotoxicity which manifests as myoclonus, delirium and then seizure. Morphine should therefore be avoided in patients with moderate to severe renal impairment but can be used cautiously and for short term in patients with mild renal impairment.
Hydromorphone (Dilaudid) is more potent (mg to mg) than morphine but has no difference in efficacy.
It is available in long-acting and short acting formulations. However, the long acting formulation is extremely expensive, not covered by most insurance and is cost-prohibitive in most cases.
Though not as neurotoxic as morphine metabolites, hydromorphone has toxic metabolites as well and is relatively contraindicated in patients with renal failure.
Hydromorphone has several drawbacks in the outpatient setting:
It is expensive and has a high street value and therefore diversion potential.
It requires the use of a different long-acting opioid for maintenance pain relief.
Oxycodone is available in long-acting (Oxycontin) and short acting formulations.
It is only available in oral formulations (pills and liquid) and not available parenterally.
The disadvantage of long-acting oxycodone is its expense as it is not yet available in a generic formulation, and therefore it is sometimes not covered by insurances. Additional drawbacks include its high potential for abuse and a high street value.
Like hydromorphone, its metabolites are less neurotoxic than morphine’s.
Fentanyl comes in many formulations including intravenous, transdermal (TD), intranasal, sublingual and buccal.
It is estimated to be eighty times (80×) more potent than morphine as an analgesic.
Its lipid solubility, high potency and low molecular weight make it ideal for administration systemically through a relatively small area of the skin or mucosa.
One of the biggest advantages of fentanyl is that its metabolites appear to be inactive, conferring neither analgesia nor toxicity. Therefore, fentanyl does not have any neurotoxicity in the setting of renal impairment as seen in the other opioids discussed above.
Table 9.2 [2] summarizes the advantages and disadvantages of TD fentanyl compared to oral or injectable opioids.
Table 9.2.
Advantages and disadvantages of transdermal fentanyl compared to oral or IV/SC opioids [2].
Transdermal fentanyl versus oral opioid
Advantages of transdermal fentanyl
Disadvantages of transdermal fentanyl
Convenience
High cost
Continuous administration
Slower onset of action
Longer duration of action
More difficult to reverse side effects
Greater patient adherence
Slow titration
Avoids PO in patients with nausea/vomiting
Possible adhesive sensitivity
Transdermal fentanyl versus continuous IV/SC opioid infusion
Advantages of transdermal fentanyl
Disadvantages of transdermal fentanyl
Less expensive
Slower onset of action
Easier for caregiver
More difficult to reverse side effects
Less invasive (no needles, no pumps)
Separate intermittent medication required for breakthrough pain
A major disadvantage of fentanyl is its expense.
The FDA Black Box warns that the transdermal patch is not intended for opioid naïve patients. Absorption into serum begins approximately 4–8 h after application; however, therapeutic blood levels are not achieved for 12–16 h with mean time to maximum concentration between 29 and 36 h.
At steady state TD fentanyl produces drug levels similar to those produced by intravenous or subcutaneous infusion with the same infusion rate.
Levels vary between patients based on individual differences in skin absorption characteristics and fentanyl clearance rates.
Patients with elevated body temperature (especially >102 °F) may experience higher than expected drug absorption and must be carefully monitored.
Switching to an alternate oral or parenteral opioid may be required. A common myth is that fentanyl patches causing less constipation than other opioids.
Methadone has several advantages but should be used in consultation with a palliative care or pain specialist.
An important advantage is that it is very inexpensive, $20 to $30 a month. Most patients can afford methadone even if it is not covered by their insurance.
Methadone has no known active metabolites and only needs to be dose adjusted when renal function drops below 10 %.
It is the only long acting opioid that comes in a liquid formulation and can therefore be given through feeding tubes or to patients with dysphagia who cannot swallow pills.
In addition to its opioid activity, methadone antagonizes the NMDA receptors, giving it a second analgesic effect.
Because of its very low potential for abuse and hence, low street value, Methadone is the safest option in patients with a history of drug abuse or at risk for opioid diversion.
Methadone metabolism differs from other opioids in that it does not follow first order pharmacokinetics.
Methadone has biphasic pharmacokinetics and therefore can be used both as a long-acting analgesic and a short-acting analgesic.
Because methadone is long acting, it is usually prescribed every 8 h in younger patients and every 12 h in older patients, when used as a maintenance analgesic.
As an as-needed, short acting analgesic, it is dosed at a minimum interval of every 3 h.
Although methadone quickly binds to the mu-opioid receptors, methadone takes 3–5 days to antagonize the NMDA-receptors and become maximally effective.
Because of this, methadone must be titrated slowly. Increasing methadone doses more frequently than every 3–5 days is strongly discouraged given the possibility for overdose when the methadone reaches steady state.
Opioid equivalency has only been established between oral morphine and methadone and uses a sliding scale that depends on the total amount of oral morphine equivalents required in 24 h (Table 9.3) [2].
24 h oral morphine dose
Oral morphine:oral methadone
<100 mg
3:1
101–300 mg
5:1
301–600 mg
10:1
601–800 mg
12:1
801–1,000 mg
15:1
>1,001 mg
20:1
This sliding scale is needed to account for its NMDA receptor blocking analgesic effect. The conversion ratio of oral to IV methadone is 2:1. Therefore the IV methadone dose is half of the oral dose.
A negative side effect more common with methadone than with other opioids is the risk for QTc-prolongation. This risk is heightened with the addition of other QTc-prolonging medications. Although the documented cases of methadone induced QTc-prolongation have occurred only in patients taking more than 150 mg a day, EKG monitoring of patients on lower doses of methadone is prudent if they are taking other QTc-prolonging medications or if they will be taking methadone for more than 6 months. QTc-prolongation with methadone is more likely in the presence of hypokalemia and hypomagnesemia.
Opioid Adverse Effects
Since every medication has side effects, the goal of opioid therapy is to titrate to analgesia while minimizing these adverse effects as much as possible.
These side effects can be addressed with the following approaches:
Use the smallest dose of opioid necessary.
Use of co-analgesics.
Treatment of the side effect, e.g., constipation.
Table 9.4 [2] lists the most common and clinically relevant opioid side effects.
Adverse effect
Management
Gastrointestinal
• Constipation
• Nausea/vomiting
• Delayed gastric emptying
• Ileus
• Prophylactic bowel regimen
• PRN suppository or enema
• Antiemetics, promotility agents
• Opioid antagonists (methylnaltrexone)
• Opioid minimizing with or without adjuvant medications
Central nervous system
• Somnolence
• Cognitive
Impairment
• Delirium
• Hyperalgesia
• Psychostimulants, opioid reduction or rotation
• Careful medication review and evaluation of medical scenario (for infection, neurologic or cardiac event)
• Antipsychotic medication (Haldol frequently used)
• Opioid reduction or rotation
Respiratory depression
• Frequent assessment and reevaluation of patient
• Prescreen patients for predisposing comorbidities and medications
• Supplemental oxygen or noninvasive positive pressure ventilation as appropriate
• Pulse oximetry
• Cautious use of dilute (1:10) naloxone if hypoxemia or respiratory rate less than or equal to 6
Cutaneous
• Pruritus
• Perspiration
• Trial of antihistamine, opioid rotation
• Icepacks
They can range from bothersome but benign to serious and fatal.
The most feared adverse effects, respiratory depression and death, are rare with good management.
Respiratory depression is more likely to occur in patients with impaired ventilation such as chronic lung disease, sleep apnea, or obesity.
Patients with concomitantly administered sedating medications such as benzodiazepines are also at higher risk for respiratory depression.
Pulse oximetry monitoring and supplemental oxygen are not helpful as hypoxemia typically occurs after apnea.
Opioid Conversion
An opioid can be safely and effectively converted to another opioid using the concept of equal analgesia, i.e., opioids are equally effective but have different potencies.
Table 9.5 [2, 3] presents an easy-to-use set of conversions.
Oral dose (mg)
IV/SC dose (mg)
Morphine
15
5
Hydromorphone
3
1
Oxycodone
10
Not available
Hydrocodone
15
Not available
Oxymorphone
5
1
Codeine
150
50
Levorphanol
2
1
While the conversion tables may give the median or the mean of that normal distribution, the user of the tables should keep in mind that a particular patient may be a fast metabolizer of one opioid and a slow metabolizer of another.
Since the prescriber cannot tell which patients are fast or slow metabolizers, a clinically more useful approach is direction of the patient’s pain control.
For example, if the patient’s pain is uncontrolled or anticipated to get worse, a more aggressive conversion should be used to achieve a higher dose.
If the patient’s pain is expected to get better, then a conversion should be used to achieve a dose on the lower end of the range.
Similarly if a non-opioid analgesic is being added, a lower conversion dose should be used.
Another variation to the equal analgesia conversion is the concept of incomplete cross tolerance.
A patient who is taking one type of opioid may have an increased or decreased analgesia when switched to a different opioid at the “equivalent” dose.
To adjust for this phenomenon and to avoid over sedation when starting a new medication, the dose can be reduced 20–30 % based on the patient’s pain control.
The manufacturer’s recommendation for converting from morphine to TD Fentanyl is listed in Table 9.6 [2].
Step 1: Sum total opioid received in 24 h and convert to oral morphine equivalents using equianalgesic table, e.g., Table 9.6
Step 2: Using the table below, select the fentanyl patch dose that corresponds to the morphine equivalent dose range that the patient is receiving
Daily morphine equivalent dose
24-h PO
Morphine (mg/day)
Equivalent
FDA approved manufacturer’s conversion
TD fentanyl dose (mcg/h)
60–134
25
135–224
50
225–314
75
315–404
100
405–494
125
495–584
150
585–674
175
675–764
200
765–854
225
855–944
250
945–1,034
275
1,035–1,124
300
This method requires conversion to an oral morphine equivalent and calculating the patient’s 24-h oral morphine requirement.
This table should not be used to convert from a fentanyl patch to another opioid.
For patients receiving a stable dose of a fentanyl IV infusion or patient controlled analgesia (PCA), the fentanyl should be converted from IV to patch at the equivalent dose and rounding down to the nearest available fentanyl patch dose (e.g., a patient receiving a stable infusion of 60 mcg/h of fentanyl should be converted to a 50 mcg/h fentanyl patch).
Non-opioid Classes of Medications
Anti-inflammatory Drugs
Many drug classes have direct or indirect anti-inflammatory effect. For example, antibiotics are effective anti-inflammatory medications by reducing the underlying infection while some antibiotics have direct anti-inflammatory effects as well.
The most commonly used anti-inflammatory drugs are steroids and non-steroidal anti-inflammatory drugs (NSAIDs).
They are generally thought of for musculoskeletal pain but are also effective for inflammatory visceral pain and some cancer pain, especially metastatic bone pain.
Glucocorticoids
Due to their strong anti-inflammatory properties, glucocorticoids are one of the best and first line choices.
The analgesic effect of steroids begins within 24–48 h and reaches its peak in 3–4 days. After 5 days the analgesic benefit diminishes and the risks of side effect increases.
Palliative care patients generally tolerate steroids better than NSAIDs. Steroids also have beneficial side effects for palliative care patients, such as increased appetite, weight gain, increased energy, decreased nausea, and decreased shortness of breath.
They can reduce the effects of brain metastases and bowel obstruction.
Dexamethasone is the steroid of choice for most palliative care patients, because it has a high anti-inflammatory potency compared to other steroids. Dexamethasone also has little mineralocorticoid effects and thus does not cause or increase edema/fluid retention. Since the analgesic effect is related to the dose and side effects are generally associated with duration, a short course, high dose burst of steroids is recommended for pain management.
Typical doses range from 12 to 20 mg per day. Even when given for only 4 or 5 days, the analgesic effect of steroids can last up to 2 weeks.
NSAIDs
For the best results, NSAIDs should be given scheduled or around the clock.
In the acute setting, short-acting NSAIDS such as ibuprofen are preferred, in case of adverse effects.
Long-acting NSAIDS, such as naproxen, are easier for patients to take as an outpatient.
For patients who are unable to take oral NSAIDs, intravenous ketoralac (Toradol) can be given.
A proton pump inhibitor should be given with high dose NSAIDs for gastric protection.
NSAIDs are contraindicated in patients with increased risk of bleeding, renal impairment, heart failure and/or uncontrolled hypertension.
Bisphosphonates
Bisphosphonates reduce bone inflammation through inhibition of osteoclast function. They are particularly effective in patients with bone pain secondary to metastases.
They are given via the intravenous route and therefore must be given in the inpatient or at an outpatient infusion center.
These doses should be repeated monthly for continued effect and adjusted for renal function.
Neuropathic Pain Agents
Tricyclic Antidepressants (TCAs)
Tricyclic antidepressants (TCAs) are still the gold standard for neuropathic pain, due to the large volume of evidence, though in practice they are not used as a first line agent.
The exact pain mechanism of TCAs is unknown.
TCAs should be dosed at night due to their sedative effects.
They are generally not tolerated by older patients due to their anticholinergic side effects.
The other major dose limiting side effect is orthostatic hypotension. Their cardiac side effects limit their use in patients with major cardiac problems.
Their multiple drug interactions also limit their use in patients on multiple medications.
Seratonin Norepinephrine Reuptake Inhibitors (SNRIs)
Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) are effective adjuvants for neuropathic pain. They are good choices for patients who also require treatment for depression but cannot take a TCA.
The doses effective for pain are often lower than those effective for depression. Just as these medications often need 2–6 weeks to reach full effect in the treatment for depression, they also require 1–2 weeks to reach full effect in the treatment of pain.
Duloxetine is approved by the Food and Drug Administration (FDA) for treatment of both pain and depression. It is not yet generic and therefore is expensive and often not covered by insurance companies as a first line treatment for neuropathic pain.
Venlafaxine has the same mechanism as Duloxetine and is equally effective for both pain and depression [4]. Venlafaxine is generic and less expensive and more likely to be covered by insurance.
Gabapentin and Pregabalin
Gabapentin is the most commonly prescribed neuropathic pain medication with a 70 % efficacy rate.
Built from the GABA (gamma-aminobutyric acid) molecule, its mechanism is not related to the GABA receptor, but instead it binds to the alpha-2-delta ligand receptor of the calcium channel on the cell membrane of neurons.
Gabapentin is started at a low and often subtherapeutic dose, because of its sedating side effect. It should be titrated over time, e.g., 2 weeks, to therapeutic effect.
Because of its sedating effect, gabapentin is a good choice for patients who have insomnia, a common complaint in pain patients.
Gabapentin is usually dosed every 8 h for seizures, but should be dosed predominately at night and at bedtime for pain to avoid daytime sedation.
For example, 25 % of the daily dose can be given in the morning, 25–50 % of the daily dose around 5–6 PM, and 50 % or more of the daily dose at bedtime.
Gabapentin is 90 % renally excreted and therefore requires dosing adjustment in patients with renal impairment.
Pregabalin is structurally similar to Gabapentin and is thought to work in the same way for the treatment of neuropathic pain.
It is not yet generic and tends to be more expensive than Gabapentin. Often, insurance companies will not cover Pregabalin unless the patient has failed Gabapentin treatment.
A small subset of patients will respond to Pregabalin when they have not responded to Gabapentin.Related posts:
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