Clinical setting

Dosagea

General principles

Opioids are very useful in the context of moderate to severe dyspnea related to advanced disease that is not controlled despite optimizing treatments and oxygen. They are generally safe if started at appropriate doses and titrated appropriately. Their usefulness and safety have been demonstrated in studies for patients with dyspnea related to cancer or noncancerous diseases (such as advanced heart, lung, renal, and neurologic diseases).

Morphine is a good and useful agent to start with when a strong opioid is required. Claims that hydromorphone is more effective than morphine and has a better adverse effect profile are not supported by evidence. The pharmacokinetics and pharmacodynamics of these 2 are very similar; some of their metabolites are active (can cause opioid toxicity) and are renally eliminated (therefore they can accumulate with significant renal impairment).

The oral route is the preferred route in most cases as it is the most practical, especially for nonhospitalized patients. Parenteral routes (SC or IV) are reserved for patients who are not able to swallow or experiencing a dyspnea (or pain) crisis and need immediate onset of action.

Starting doses of opioids are smaller and the intervals between doses are longer when patients have advanced frailty or age, or heart, lung, renal, and/or neurologic diseases. Dose titrations are also more gradual (over many days rather than daily or every few days).

The more common adverse effects of a regular opioid regimen are constipation, nausea, and somnolence. Constipation does not resolve spontaneously, so a laxative (senna, lactulose, or polyethylene glycol) is required as long as the patient is on an opioid. Nausea, if present, usually resolves after a few days. Upon starting the opioid, an as-needed dose of metoclopramide or domperidone can be ordered (eg, 10 mg tid PO as needed). Somnolence also usually resolves after a few days. Encourage patients to rest and drink fluids. If constipation is very severe, reduction of the opioid dose may be needed.

Provide education on opioids to patients and families, including the adverse effects to expect. Advise them not to drive or operate any machinery while opioids are being started, increased, or titrated (this can be started once there are no adverse effects).

Titration of the dose is often required initially to identify the optimal dose for the patient. Initial titration can be done over several days or a few weeks, with the goal of achieving control of dyspnea (or pain) without intolerable adverse effects. Titration involves increasing the dose by ~25% to 50% (and sometimes even higher in the lower dose ranges). Titration is slower in patients who have frailty or advanced heart, lung, renal, and/or neurologic diseases.

Titration is very variable from patient to patient and depends on circumstances. Once the right dose is found for a patient, the opioid can be changed to a slow-release (controlled release) formulation, as this is more convenient for the patient (eg, no need to wake during the night to take a dose).

Dose increases over time are also sometimes required to maintain effect in the presence of progressing disease and development of tolerance to the opioid.

If parenteral opioids are required, the SC route is as effective as the IV route (and often more convenient). The SC route is about twice more equipotent than the oral route (divide the oral dose by 2 for the SC equivalent), and the IV route is ~2 to 3 times more equipotent than the oral route (divide the oral dose by 2 or 3) for the conversion.

Opioid neurotoxicity versus opioid overdose: Opioid neurotoxicity is an opioid adverse effect that has to be differentiated from an overdose (or narcotization). Their clinical presentations and management are different. Opioid neurotoxicity presents clinically with ≥1 of the following: myoclonus, cognitive impairment, hallucinations, agitation or motor retardation, somnolence, hyperalgesia or allodynia. The management is relatively straightforward and consists of switching to a different opioid (eg, morphine to hydromorphone, or vice versa, if dyspnea or pain are not well controlled and if the toxicity is moderate to severe) or reducing the opioid (if pain or dyspnea are well controlled and the toxicity is mild). An opioid overdose presents with the classical triad of respiratory depression, miosis, and reduced level of consciousness. If severe and life threatening, administer naloxone and withhold the opioid temporarily. Once resolved, restart the opioid to avoid withdrawal with an exacerbation of pain or dyspnea but at a lower dose than previously (~30% to 50% lower and then titrate to effect again). If mild, one may simply withhold the next opioid doses and restart at a lower dose (~20% to 30% lower).

Respiratory depression is exceptionally rare when these principles of opioid use are adhered to (namely, appropriate starting doses and appropriate titration).

Screen for opioid use disorder or risk of opioid diversion prior to initiating an opioid. The Opioid Risk Tool is a simple tool to help with screening. If positive or if there are concerns about possible opioid diversion, implement strategies to mitigate. These include a contract (in which the patient will have a single prescriber, will not misplace opioid prescriptions, will not deviate from prescribed doses), do not prescribe breakthrough as-needed dosing, dispense in small amounts, and order periodic urine testing for drugs.

Opioid-naive patients with none of the following:

– Advanced heart, lung, renal or neurological diseases

– Very advanced age

– Advanced frailty

The selection of the opioid type and the starting dose is similar as in the management of cancer pain. Morphine remains a good starting opioid in these situations.

Morphine: Start with morphine immediate release formulation 5 mg PO every 4 hours plus a breakthrough dose of 2.5 mg or 5 mg PO every 2 hours as needed. In some cases this starting dose relieves dyspnea. If not, the dose is titrated daily or every 2-3 days (proportionately to the level of dyspnea and how the patient is tolerating the opioid and the dose increases). When dose titration is needed, dose increases of up to 50% are usually well tolerated, but slower or smaller dose titrations may be needed in more frail patients or if the patient is experiencing somnolence.

Once the optimal dose is achieved (usually after several days or a 1-2-week titration) when dyspnea or pain are well controlled and there are no significant adverse effects, the opioid can be switched to a long-acting formulation (slow-release formulation). The total daily dose of the slow-acting form should be equivalent or as close as possible to the daily opioid dose of the immediate-release formulation used.

Breakthrough doses are usually one-sixth to one-tenth of the regular total daily dose. Patients should be instructed to contact the prescribing clinician for reassessment and probable dose adjustment if >3 breakthrough doses have been used within 24 hours.

If the patient is truly allergic to morphine (which is rare), an alternative option could be hydromorphone or oxycodone. The principles of dosing are as described above. The starting dose of hydromorphone (immediate release) is 1 mg PO every 4 hours and breakthrough doses of 0.5 mg or 1 mg PO every 2 hours as needed.

Opioid-naive patients with ≥1 of the following conditions:

– Advanced heart, lung, renal, or neurologic diseases

– Very advanced age

– Advanced frailty