Opioids Give Safe Pain Relief for Cancer Patients

CLEVELAND, March 22 -- Concerns that morphine or other opioids will cause respiratory depression when given to cancer patients for pain are unfounded, researchers here asserted.

During titration of parenteral opioids for relief of severe pain in various forms of cancer, there was no evidence of significant respiratory depression, as measured by end-tidal CO₂, found Bassam Estfan, M.D., of the Cleveland Clinic, and colleagues.

"Although 80% to 90% of cancer pain can be controlled with opioids, suboptimal pain control is common because under-prescribing remains a major barrier," the authors wrote in the March issue of Palliative Medicine.

Many clinicians are reluctant to use adequate doses of the drugs to alleviate pain, out of concern that aggressive use of opioids could hasten death or lead to other problems such as substance abuse, diversion of drugs to others, hemodynamic instability, CNS toxicity, and respiratory depression, the investigators wrote.

"Contrary to this belief, numerous studies and reviews of opioids and sedatives worldwide are clear that they do not hasten death or alter survival," wrote Rob George, M.D., a consultant in palliative medicine at University College London, and Claud Regnard, M.D., a consultant in palliative care at St. Oswald's Hospice in Gosforth, Newcastle-upon-Tyne, in England, in an accompanying editorial.

"When given after withdrawing ventilator support they do not hasten death. Indeed, even in those fully dependent on mechanical support, opioids and benzodiazepines enable breathing to be more comfortable and to continue longer after ventilatory withdrawal, due to their beneficial effect on respiratory efficiency," the editorialists wrote.

In their study, the Cleveland Clinic team monitored 30 cancer patients for changes in respiratory parameters during parenteral opioid titration for cancer pain.

The study group consisted of 17 women and 13 men from the ages of 29 to 85 with various solid-organ and hematologic malignancies.

Fourteen of the patients had known metastases, and 18 had poor performance status as defined by an Eastern Cooperative Oncology Group (ECOG) score of 3 or 4. Four patients also had pulmonary disease (one each of bronchitis, asthma, pleural effusion, and radiation pneumonitis). Thirteen patients were on morphine before being enrolled in the study, six were on fentanyl, four were on oxycodone, and one patient each was on methadone and hydromorphone. The remaining five had not received opioids.

Patients were excluded if they had been on oxygen at home prior to admission, or if they received oxygen supplementation during opioid titration.

The main study endpoint was the change in end-tidal CO₂ between initiation of opioid titration and pain control. Secondary outcomes included changes in respiratory rate, oxygen saturation, clinical respiratory depression, sedation, delirium, and the need for arterial blood gas monitoring.

The patients were monitored daily for end-tidal CO₂, oxygen saturation, respiratory rate and vital signs until pain control was achieved. Pain control was defined as a score of 4 or less on a scale of 0 (no pain) to 10 (severe pain), and four or fewer breakthrough opioid doses within the previous 24 hours for non-incident pain.

The authors found that of the 29 patients for whom results were available, mean end-tidal CO₂ at baseline was 33.49 + 5.0 mm Hg compared with 34.79 + 5.7 mm Hg at the point of adequate pain control (P=0.14, 95% confidence interval -0.5 to 3.3). None of the patients had an end-tidal CO₂ > 49 mm Hg.

In addition, all of the patients maintained and O₂ saturation of at least/92% In two patients the respiratory rate dropped transiently to eight per minute in one patient and nine per minute in the other.

These patients recovered spontaneously without the need for dose modification, and their respiratory rates remained above 10 per minute for the remainder of the study. None of the patients in the study required arterial blood gas measurements for either hypercapnia or hyperoxia.

"Titration of parenteral opioids for relief of moderate to severe cancer pain was not associated with clinical or objective evidence of respiration depression," the authors concluded. "Gas exchange need not be monitored routinely when parenteral opioids are titrated to pain control."

In their editorial, Dr. George and Dr. Regnard said that the study demonstrates that "even rapid titration to high doses for severe cancer pain, when done properly, does not cause clinically significant respiratory depression. In the treatment of dyspnea there is no evidence that the doses of systemic opioids used in palliative care cause respiratory depression. These findings also explain why opioids and benzodiazepines are considered the least likely agents to be used for euthanasia in The Netherlands."

Dr. Estfan and colleagues said their study was limited by the exclusion of oxygen-dependent patients and by the single daily measurement to assess respiratory function. In addition, they did not measure end-tidal CO₂ in those patients who were withdrawn from the study because they developed delirium, and therefore may have missed hypercapnia as a cause.