2.3.1 Commonly Used Opioids (in the United States)

Table 2.2 summarizes the opioid medications that are commonly used in the United States. Morphine is the gold-standard opioid. It is available in short-acting and long-acting formulations. The benefits of morphine are that it is relatively inexpensive, is available in a liquid formulation, is ubiquitous, and is well known. Its familiarity translates to less medication errors in the hospital compared with other opioids. The liquid formulation is good for people who cannot swallow pills, have a tube feeding, or have poor bowel absorption (e.g., short bowel). Morphine is metabolized and glucuronidated 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 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 insurance and cost prohibitive in most cases. Though not as neurotoxic as morphine, hydromorphone has toxic metabolites as well and is relatively contraindicated in patients with renal failure. The drawback of hydromorphone is its expense and the need to use a different opioid for long-acting 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 in IV formulations. The disadvantage of long-acting oxycodone is its expense as it is not yet available in a generic formulation and therefore sometimes not covered by insurance. Additional drawbacks to long-acting oxycodone are 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 80 times 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 the neurotoxicity in the setting of renal impairment as seen in the other opioids listed earlier. Table 2.3 summarizes the advantages and disadvantages of TD fentanyl compared to orally and IV or SC administered opioids. A major disadvantage of fentanyl is its expense. Its absorption is unpredictable in cachectic patients and should not be used in this population. The Food and Drug Administration (FDA) black box warns that the TD 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 to 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) must be carefully monitored and may need to be switched to an alternate oral or parenteral opioid. Fentanyl patches causing less constipation than other opioids is a myth. All opioids cause the same side effects.

2.3.2 Methadone Friend or Foe?

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–$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 also antagonizes the N-methyl-d-aspartate (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 a biphasic pharmacokinetics: its opioid (first phase or plasma) effects peak in 2–3 h; its NMDA receptor antagonism (second phase or tissue) effect has an individually variable and long half-life and resultant peak. Therefore, methadone 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 used similar to other short-acting opioids. 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 2.4). This sliding scale is needed to account for its NMDA receptor blocking analgesic effect. As with all other opioids, there are variations of conversion tables in textbooks and online. The conversion ratio of oral to IV methadone is 2:1. Therefore, the IV methadone dose is half of the oral dose.

If overdosed, methadone requires a naloxone infusion to reverse. A negative side effect more common with methadone than 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, electrocardiogram (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.

2.3.3 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 effects can be addressed with the following approaches: (1) dose reduction of the prescribed opioid, (2) rotation to an equianalgesic dose of a different opioid, or (3) treatment of the side effect (e.g., constipation). Table 2.5 lists the most common and clinically relevant opioid side effects. They can range from bothersome but benign to serious and fatal. Though rare, the most feared adverse effects are respiratory depression and death. 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 though reassuring on the surface does not reduce the risk of respiratory depression. Supplemental oxygen is not helpful as hypoxemia typically occur after hypercapnia.

2.3.4 Opioid Titration

Opioid titration is usually necessary in the management of pain in the hospital. There is no theoretical dose ceiling as long as opioids are titrated safely. However, practically speaking, most opioids are limited in their dose by the neurotoxic effect of their metabolites.

The use of an intravenous opioid is the most rapid way to provide pain relief for a patient who has poorly controlled acute pain. All IV opioids are short acting with the exception of methadone. If a patient is still in severe pain 30 min after administration of IV pain medication, the dose can be doubled and given again. This can be repeated until the patient is comfortable or until the patient begins to experience side effects from the medication. For patients in severe pain, titration is best achieved with PCA (see following section).

To control a pain exacerbation, the short-acting oral formulation of an opioid can be used in patients who are able to take oral medications. Long-acting formulations are useful once initial pain control is achieved and the 24 h opioid requirement is known. Long-acting formulations should not be used for rapid titration of pain medications during a pain exacerbation. For patients in severe pain, oral opioid doses can be given every 60 min to control pain. If a patient is still in severe pain 60 min after administration of oral pain medication, the dose can be doubled and given again. This can be repeated until the patient is comfortable or until the patient begins to experience side effects from the medication.

Long-acting opioids are preferred over short-acting opioids for the management of chronic pain, based on the principle that “an ounce of prevention is better than a pound of cure.” The use of long-acting opioids allows a patient to sleep through the night without waking up to take their pain medication. Long-acting medications should be prescribed as scheduled medications as they require consistent dosing to maintain steady state. An effective starting dose of long-acting opioid is based on the total amount of opioid required in 24 h to make a patient comfortable. By using the total 24 h dose to establish a long-acting regimen, the patient receives what they have already tolerated in 24 h, thus reducing the potential for overdose while providing pain relief for the patient. Most long-acting opioids are dosed every 12 h. However, for patients who are fast metabolizers of the opioid, they may experience end of dose failure and require every 8 h dosing. If an opioid-tolerant patient presents with a pain exacerbation, an appropriate initial titration would be to increase their usual long-acting opioid by 50–100%, for example, for a patient taking ER morphine 30 mg orally every 12 h, an initial titration would be to 45 mg orally every 12 h for mild pain or 60 mg orally every 12 h for moderate or severe pain. Extended-release medications cannot be crushed and given via feeding tubes. For patients who have chronic pain, short-acting opioids can be given regularly every 4 h, in addition to as-needed doses, to provide around-the-clock coverage.

An ideal opioid regimen for a patient with chronic pain consists of a long-acting opioid to cover continuous pain and a short-acting opioid prescribed for as-needed use to cover breakthrough, incidental, or acute pain. Short-acting opioids are usually dosed every 2–4 h. A good rule of thumb for the breakthrough medication dose is 10% of the 24 h maintenance dose for each as-needed dose. If a patient is consistently requiring more than 3 doses in 24 h, they will need an increase in their long-acting medication.

2.3.5 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). Multiple equal analgesic conversion tables are available (Table 2.1). Table 2.6 presents an easy-to-use set of conversions. The variations between conversion tables come from the fact that the conversions are actually a range and not a single number as the tables suggest. The range comes from the normal distribution of metabolism of the opioids in a population. While the 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 yet 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 nonopioid analgesic is being added, a lower conversion dose should be used.