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Current Management of Opioid-Related Side Effects

Current Management of Opioid-Related Side Effects

Dr. O’Mahony and coauthors are to be congratulated on a detailed summary of this issue from both a clinical and academic perspective. There are areas, however, where I believe there should be a different emphasis, or opinions stated with which I disagree.

Unaddressed Issues

One issue not addressed in the article is the problem of information from studies in opioids for pain that is not caused by cancer. Another is studies in cancer patients in whom the pain pathophysiology, eg, postoperative pain, is not from the cancer.[1] I do not accept that these are appropriate scenarios for examining the efficacy or side effects of an opioid for cancer pain.

The most important issue that the article fails to discuss is the importance of the specificity and individualization of opioid dosing to prevent side-effects. In fact, studies that might inform such a discussion—those that systematically examine opioid side effects, examine metabolites of commonly used opioids, and compare the efficacy and side effects of agonist opioids—are lacking.

It is important to distinguish between the frequency and severity of symptoms. A minor symptom that is persistent may be more troubling than one of greater severity that is intermittent.[2] The authors refer to validated instruments for patient assessment; these are problematic because of the burden placed on patients for data collection (particularly the seriously ill) and because many instruments are unsatisfactory for methodologic and psychometric reasons.


Notably, few differences in efficacy and side effects among agonist opioids have been reported in the available literature. Morphine and hydromorphone appear to have comparable efficacy and side effects except in the area of opioid-induced itch.[3] However, to attribute the differences in side effects among the agonist opioids to either their receptor interactions or metabolites is speculative. We know little about these issues during chronic dosing or, for that matter, about the interaction between these metabolites and receptors.

Nausea and Vomiting

The statement that there is no evidence suggesting that one mu-agonist is any less emetic than another is too strong; oxycodone may be less emetic than morphine.[4] I was unsure what was being recommended with observer-rated measures of nausea, as these are subjective and can only be assessed by the patient. An important area not referred to is the effect of female gender on nausea and vomiting.

For management of nausea and vomiting, another strategy is simply to change the formulation of a specific opioid, eg, from sustained-release to immediate-release morphine. Another is to administer oral opioids after food. It is important to discontinue nonessential medications but equally important to remember the value of adjuvant analgesics. For example, if an opioid is causing significant nausea and vomiting, it may be more important to increase nonsteroidal anti-inflammatory agents than to discontinue them.

I disagree with the recommendations concerning antiemetics. Metoclopramide is the drug of choice for opioid-induced nausea and vomiting.[5] This holds true unless there are significant associated neuropsychological symptoms, in which case, haloperidol should be given.


With regard to constipation, I was surprised the authors did not refer to codeine. There are specific primary cancer sites associated with a higher risk of bowel obstruction (abdominal carcinomatosis, cancer of the ovary and pancreas). Codeine is more constipating than other agonist opioids and in my view, should not be routinely used because of this. Moreover, there is evidence that fentanyl and methadone are less constipating than morphine, and if opioid rotation is contemplated, preference should be given to them.

I disagree with dietary fiber as an initial strategy for constipation prophylaxis. All patients started on regular opioids should be prescribed laxatives simultaneously. Bulk laxatives are inappropriate because of the frequency of early satiety. Patient education is essential for effective laxative use, as are regular checks on compliance.

I believe the classification of laxatives—eg, the reference to magnesium oxide as a lubricant laxative—would not meet general acceptance. Again, adjuvant analgesics are important; powerful nonopioid analgesics such as ketorolac can be used to reduce opioid dose and improve the opioid bowel syndrome.[6]

I agree that laxative combinations are important but feel that different drugs are better employed and at higher doses.[1] Fecal incontinence in the frail elderly should be mentioned as a side effect of stimulant laxatives.

Cognitive Side Effects

The reference to "paradoxical pain" with increasing doses of opioids raises an important issue about the quality of opioid prescribing. Another interpretation of this phenomenon is that the wrong dose has been chosen, and as a result, the patient is delirious and misreporting pain. This occurs commonly when the prescriber has failed to distinguish between intermittent (often incident) and continuous pain. Consequently, the patient is being dosed around the clock for pain that is intermittent, and excess neuropsychological side effects develop. We also have evidence that there are route-related differences in morphine metabolism[7] that may affect cognitive function.

I disagree with empiric opioid rotation as an initial maneuver. The frequent recommendation to rotate opioids may actually cause a deterioration in analgesic management. Indeed, the data to support opioid rotation as a routine strategy are speculative. Cognitive side effects are partly dependent on dosing skill. Before rotation, the most important strategy is to check that current opioid dosing is correct and tailored to the pain pattern and pathophysiology. I agree with the recommendations that methylphenidate be prescribed to counter sedation, but not for other neuropsychological symptoms. I also take issue with the apparent recommendation that tricyclic antidepressants be used to manage opioid-related cognitive deficits. I feel these agents (particularly amitriptyline) should be avoided because of their cognitive side effects.


There is a possible link between myoclonus and normorphine that the authors did not identify. Myoclonus may also be a manifestation of carbon dioxide retention or a toxicity of other commonly prescribed drugs, including tricyclic antidepressants.[8]

Respiratory Depression

I disagree that respiratory depression is greatest in the opioid naive. This problem most frequently arises in those who develop intercurrent cardiorespiratory or metabolic illnesses, have inappropriate changes in opioid dosing, or are prescribed concomitant sedative medications without respiratory function being considered. The only relevant published study, which was conducted in hospice patients, did not show significant ventilatory impairment from morphine.[9] The issue of interventions with nonopioid analgesics that may precipitate respiratory depression is not given sufficient weight as a possible precipitant.[10]

The Management Algorithms

I disagree with the concept of oral laxative monotherapy for constipation, as mentioned above (Figure 2 of the article by Dr. O’Mahony et al). Management of impaction should include nitroglycerin paste or nitroglycerin tablets to treat perianal spasm.

Figure 3 illustrates the protocol for sedation. The use of psychostimulants before opioid dosing adjustments is unwise. If pain is well controlled, there should first be a reduction in the basal rate. If this is ineffective or impossible, psychostimulants should then be added. Assessment must include a review of the appropriateness of the opioids prescribed.

To prevent cognitive impairment, the authors suggest that the opioid dose be reduced after pharmacotherapy (Figure 4). If pain control is adequate, the opioid dose should be reduced or respecified to the current pain pattern. This should be done before pharmacotherapy or opioid rotation. I disagree with the use of benzodiazepines and phenothiazines here, given their sedative effects. The drug of choice is haloperidol.


1. Walsh D: Pharmacological management of cancer pain. Semin Oncol 27(1):45-63, 2000.

2. Glare P, Walsh D, Nelson K, et al: Common symptoms in patients taking morphine for chronic cancer pain: A prospective study. J Pain Symptom Manage (in press, 2000)

3. Katcher J, Walsh D: Opioid-induced itching: Morphine sulfate and hydromorphone hydrochloride. J Pain Symptom Manage 17(1):70-72, 1999.

4. Glare P, Walsh D: Dose-ranging study of oxycodone for chronic pain in advanced cancer. J Clin Oncol 11(5):973-978, 1993.

5. David MP, Walsh D: Treatment of nausea and vomiting in advanced cancer. Support Care Cancer 8:444-452, 2000.

6. Joishy S, Walsh D: The opioid-sparing effects of intravenous Ketorolac as an adjuvant analgesic in cancer pain: Application in bone metastases and the opioid bowel syndrome. J Pain Symptom Manage 16(5):334-339, 1998.

7. Glare P, Walsh D: Clinical pharmacokinetics of morphine. Ther Drug Monit 13(1):1-23, 1991.

8. Sarhill N, Walsh D, David M, et al: Methadone-induced myoclonus. Am J Hospice Pall Care (in press, 2000).

9. Walsh TD: Opiates and respiratory function in advanced cancer. Recent Results Cancer Res 89:115-117, 1984.

10. Quevedo F, Walsh D: Morphine-induced ventilatory failure after spinal cord compression. J Pain Symptom Manage 18(2):140-142, 1999.

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