What Principles Should Guide Opioid Dose Conversions?

Oral

Whenever practical, the oral route is preferred as oral formulations are widely available and relatively inexpensive. Short-acting (immediate-release) opioids are often prescribed for acute and breakthrough pain on an as-needed basis and may also be administered around the clock for chronic or persistent pain. Some short-acting opioids are combined with acetaminophen or an NSAID, and these combinations have dose limitations imposed by the nonopioid component. Long-acting (modified- or sustained-release) oral opioids are formulated to gradually release the medication in the gastrointestinal tract, are appropriate for chronic and persistent pain only, and may improve pain relief, sleep, and adherence. Usually, opioid regimens for chronic pain include a long-acting opioid plus a supplemental short-acting opioid for treatment of breakthrough pain. Patients who have an impaired ability to swallow or to absorb oral medications may be better served by using other routes. Relative contraindications to the oral route include difficulty swallowing, nausea, vomiting, malignant bowel obstruction, short gut syndrome, gastroparesis, or those with enterostomies. A further limitation of oral opioids is that they take longer to relieve pain than the intravenous route and have a longer half-life. The slow onset of effect may make oral opioids less effective for breakthrough or activity-provoked pain, which may be brief and resolved by the time the oral opioid has reached peak effect. The longer half-life relative to intravenous opioids means doses cannot be titrated as frequently, especially in the outpatient setting or in the community. If rapid escalation of opioids is needed in an acute care setting, the dose may be titrated intravenously, and the patient transitioned back to an oral regimen when a stable effective dose is achieved. A summary of indications for oral administration of opioids can be found in Table 2.1 .

Intravenous

There are three characteristics of intravenous opioids that can help guide the clinician in choosing when to prescribe them: (1) a short onset time and time to peak effect can be beneficial when rapid pain relief is desired (e.g., in a pain crisis or for breakthrough pain that is sudden and severe); (2) a short half-life means the dose may be titrated more frequently, which can be useful for dose-finding in patients with severe pain; and (3) the relatively high potency of intravenous opioids may be advantageous when very high doses make other routes impractical. Intravenous opioids are commonly administered by intermittent injection, by continuous infusion, or via a patient-controlled analgesia (PCA) pump (see Chapter 3 ). Intravenous administration via intermittent injection is helpful for acute pain, breakthrough pain, and exacerbations of chronic pain. Continuous intravenous infusion should be used only in opioid-tolerant patients for chronic or persistent pain that requires around-the-clock administration. Intravenous PCA pumps have options for continuous infusion as well as intermittent bolus injections on patient or clinician demand. PCA pumps are useful in a variety of inpatient and occasionally outpatient settings, including patients with acute, postoperative, and chronic pain. When studying pain relief in patients receiving intravenous or oral opioids, Elsner and colleagues found that 87% of the patients in the intravenous group reported sufficient pain relief after 1 hour, compared with only 26% in the oral group. The proportion of patients experiencing pain relief was higher in the intravenous group, despite this group having higher initial scores of pain intensity. Intravenous delivery requires closer supervision and monitoring than other routes, which may necessitate an inpatient setting. Despite these complexities, rapid control of escalating pain or breakthrough pain is most effectively accomplished using the parenteral route of opioid administration.

Transmucosal: Buccal, Sublingual, or Nasal

The transmucosal route of delivery offers several advantages. The buccal, sublingual, and nasal mucosal tissues are densely vascularized and more permeable than the skin. Moreover, the oral and nasal cavities have a relatively uniform temperature and a large surface area, further optimizing this delivery route. Lipophilic, un-ionized opioids, such as fentanyl, pass through the cellular membranes relatively readily, traveling rapidly through the mucosa into the bloodstream. Other opioids, such as morphine, oxycodone, and hydromorphone, are strongly hydrophilic and less able to traverse the mucosa.

Because fentanyl is highly lipophilic, numerous transmucosal formulations have been developed, including lozenges, tablets, films, and sprays. These formulations are appropriate only for opioid-tolerant patients who require an opioid for breakthrough pain. Oral liquid formulations for morphine, oxycodone, and hydromorphone are widely available and may be administered sublingually, however the available evidence shows limited and widely variable transmucosal absorption. It is likely that observed analgesic effects of these hydrophilic opioids result in large part from swallowed medication. Clinicians should expect unpredictable effects, especially for patients who cannot swallow, and should use caution when calculating equivalent doses involving transmucosal opioids.

The short-acting buccal fentanyl tablet (Fentora) offers an onset of pain relief in as little as 15 minutes and a duration of analgesic effect of approximately 60 minutes. The buccal tablet is 65% bioavailable and is indicated for management of breakthrough pain in patients who are opioid tolerant, which is defined as those taking the equivalent of at least 60 mg of oral morphine per day. The oral transmucosal fentanyl citrate lozenge (Actiq) is another short-acting formulation of fentanyl. The lozenge must be gently rubbed against the buccal mucosa until it has completely dissolved and requires active patient participation to correctly use the lozenge. Clinicians must start transmucosal fentanyl no higher than the initial dose recommended by the manufacturer regardless of the patient’s opioid history. Similarly, titration should follow the manufacturer’s recommendations, which differ depending on the formulation. Clinicians must not attempt to calculate equianalgesic doses of transmucosal fentanyl. Because of the high potency and the high risk for adverse effects, transmucosal fentanyl formulations are restricted in the United States to use for breakthrough cancer pain in adults who are already taking around-the-clock opioids for pain. Both patients and prescribers must register in a federally mandated Risk Evaluation and Mitigation Strategy (REMS) program for transmucosal fentanyl to be prescribed to outpatients. Furthermore, these transmucosal formulations of fentanyl are expensive, particularly compared to other opioid preparations, and many forms of insurance will not cover transmucosal fentanyl as a first-line opioid.

Morphine is one of the most used transmucosal opioids, despite evidence that it may not be as effective as other opioids. It is poorly absorbed across the oral mucosa because of its low lipid solubility and extensive ionization at typical oral pH. Studies indicate that sublingual morphine has bioavailability of approximately 20%, compared to approximately 50% for fentanyl. A variety of concentrations of oral liquid morphine, hydromorphone, and oxycodone are manufactured in the United States; however, local availability varies, and clinicians will need to contact pharmacies to ensure that prescriptions can be filled. The more concentrated formulations (such as morphine 20 mg/mL) are useful in patients who are not able to tolerate oral administration and who do not have convenient intravenous access. These forms of oral opioids are often used in patients in hospice care, who may have difficulty swallowing and are approaching the end of their lives.