Avoiding Respiratory Depression With Opiate Use

Scott Lothian, RPh


July 13, 2010


Can you comment on the risk for respiratory depression and strategies to minimize this risk when using opiates in "tolerant" patients?

Response from Scott Lothian, RPh
Clinical Pharmacist, Oncology & Pain Management; Analyst, Clinical Information Services, Northwestern Memorial Hospital, Chicago, Illinois

The presence of pain is the indication for opioid therapy. It seems like a simple concept, but it is the "pain impulse" that drives the respiratory center during therapy. This, along with eventual tolerance, is what makes the safe use of opioids possible. When opioids are used in the absence of pain, the respiratory center is much more sensitive to opioid adverse effects.

Initial opioid therapy is marked with side effects (eg, sedation, nausea, constipation). These side effects vary and can be treated with multiple agents for symptom relief. With continued opioid use (after several days or more) most patients will become tolerant to side effects; the exception is constipation, which requires continued prophylaxis.

Respiratory depression (RD) is certainly the most serious opioid adverse event, but in general RD is most concerning when large opioid doses are required in an opioid-naive patient with severe pain (especially if this pain is short-lived or self-resolving). However, as with most of the other side effects, patients quickly become tolerant to the opioid's effect on the respiratory center. RD is, at best, difficult to induce after therapy has been established. But difficult does not mean impossible.

Opioid-naive patients aside, RD could be a concern in patients receiving sustained-release agents who have decreasing pain. However, it is unlikely. A patient well-established on opioids for chronic pain, or even a tolerant patient who does not have chronic pain, would likely not increase his or her dose quickly enough to cause RD. Sedation always occurs before RD, and a patient with decreasing pain would feel sluggish or drowsy with the current opioid dose well before somnolence or RD occurred. Also, the reappearance of these side effects should indicate to the patient and physician that dose titration is needed. However, if a patient is receiving a longer-duration opioid product (eg, transdermal fentanyl patch or basal infusion with or without a demand dose), this drowsiness may eventually progress to somnolence and RD if this scenario is not identified.

Rule: Longer-duration opioid products are for patients with well-defined, chronic pain (usually with stable dosing or requiring eventual upward titration).

Rule: Use short-duration SR products (ie, every 8-24 hours) for patients who are likely to have decreasing pain (or as a baseline for initial titration in the above scenario.

In all patients with decreasing pain, use the "as-needed" portion of their therapy as a buffer, where decreasing "as-needed" use may indicate the need to decrease the sustained-release dose. This is especially important for surgery or procedures that may eventually decrease the patient's pain. Whereas the baseline opioid in a patient with chronic pain may cover 100% of the pain, a patient with decreasing pain should have only 50%-75% baseline coverage (depending on the clinical situation).

The following case scenarios further illustrate effective use of opioids in patients with pain.

Case 1

A patient with breast cancer is receiving established patient-controlled analgesia (PCA) (basal and demand dose) after chemotherapy and pamidronate treatment. When it became clear that the family was continuing to "push the button for her" because she was too sleepy, the PCA was held and eventually stopped altogether. The patient finally awoke without the need for a PCA. The patient's pain had resolved, causing severe somnolence but no RD.

In any patient, the balance of the opioid effect (independent of dose) and the pain impulse is critical. For the opioid-naive patients, this window is initially narrow, but it becomes very forgiving as the patient develops tolerance. When combined with an opioid, an adjuvant can be additive or even synergistic for almost any type of pain control. As with naturally decreasing pain, the addition of an appropriate adjuvant may so profoundly decrease the patient's pain impulse that it disrupts the balance between the pain and the current opioid dose, causing the reemergence of side effects.

Rule: Always assess the quality or character of the patient's pain when selecting the proper agents. It is often best to combine appropriate agents at lower doses than to maximize the dose of one agent before switching to or adding another.

Case 2

A patient with postherpetic neuralgia is receiving the maximum dose of gabapentin and is experiencing sedation and confusion. The dose was tapered to 300 mg twice daily. After the integration of a low-dose opioid and nortriptyline, 25 mg once daily at bedtime, the patient reported minimal sedation and better control.

Case 3

A patient with breast cancer and bony metastases whose pain was well controlled had naproxen added to her regimen. She became confused and combative until her opioid dose was decreased by 50%. Her pain remained well controlled at this lower dose.

As illustrated in cases 2 and 3, uncontrolled anxiety or depression can severely thwart pain control. Resolution of chronic underlying anxiety and depression may greatly decrease pain and opioid requirements. In contrast, in patients who have developed these issues with their pain, good pain control may completely resolve their symptoms. With this in mind, anxiety, depression, and drug withdrawal can vastly increase a patient's opioid intake during titration of therapy, leading to opioid intake that is not supported by pain alone. Eventual resolution of anxiety and depression can cause the pain/opioid balance to shift and side effects to reemerge.

Rule: Fully assess patients to identify the presence of these issues and treat as indicated, noting that onset of anxiety and depression with pain may resolve with pain control.

  • Anxiety, more so than depression, may require short-term treatment during initial opioid titration.

  • A nicotine patch is certainly indicated in active smokers.

  • Appropriate continuation of benzodiazepines or other agents contributing to possible withdrawal is important.

Case 4

An older woman who has undergone neck surgery continued to require escalation of the PCA dose. Low-dose lorazepam was eventually added (0.5 mg every 8 hours via intravenous [IV] push). Confusion and somnolence developed after the third lorazepam dose, and RD occurred after the fourth dose. The PCA was held and then discontinued; her pain was eventually controlled with less than 10% of her previous opioid dose. She was later found to have a presurgical history of smoking and benzodiazepine use, which escalated her initial opioid requirements.

Pharmacokinetics should be in the back of every clinician's mind. For example, peak effect, duration of action, drug-drug interactions, and organ function should always be considered when assessing or planning a patient's therapy. Most commonly used opioids (morphine, hydromorphone, and oxycodone) have a similar peak (IV = about 10 minutes; oral = about 60 minutes) and duration (IV = 2-3 hours; oral = 3-4 hours).

RD is most problematic during the peak concentration of the opioid. For example, if a patient is breathing 10 times per minute 2 hours after an oral morphine dose, he or she is not likely to have RD issues. However, when other agents are in the mix, patient pharmacokinetics must be considered.

Rule: When assessing a patient with somnolence or RD, you must know all of his or her medications and when they were administered.

Rule: Patients receiving long-term opioid therapy must be told that they should not take other agents without the knowledge of their physician.


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