Study

Opioids are the mainstay of cancer pain management in the developed world, but many patients with cancer have persistent pain despite treatment with strong opioids. According to a recent study, acetaminophen can improve pain management in these patients. Standard recommendations are to titrate the dose of opioids to get the best balance between dose-dependent analgesia and side effects, note the researchers, led by Martin Stockler, MD, Co-Director of Cancer Trials for the Australian National Health and Medical Research Council and Senior Lecturer in Cancer Medicine and Clinical Epidemiology at the University of Sydney. The study, published in the Journal of Clinical Oncology (2004;22:3389–3394), compared opioid treatment with and without acetaminophen and concluded that the analgesic improved pain relief and well-being without major side effects in these patients. “Its [acetaminophen's] addition is worth considering in all such patients,” Dr. Stockler said in an interview. “Typically, the optimal opioid dose relieves pain substantially but not completely, because subjective side effects become troublesome. If higher doses were used regularly, patients would be excessively drowsy, nauseated, etc.” Improve Balance between Analgesia & Side Effects Dr. Stockler said the rationale for adding acetaminophen to a strong opioid regimen is to improve the balance between analgesia and side effects by either increasing analgesia without adding side effects, or by maintaining analgesia with fewer side effects from opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), or other drugs. He said acetaminophen (called paracetamol in the UK and Australia and other parts of the world) is frequently added to strong opioids in the UK and Australia to improve analgesia in such cases, but in North America is often used only with weak opioids.Figure: Martin Stockler, MD, noted that acetaminophen—called paracetamol in the UK and Australia—is frequently added to strong opioids there to improve analgesia in such cases, but in North America acetaminophen is generally used only with weak opioids for such patients. “Acetaminophen's addition is worth considering….Typically, the optimal opioid dose relieves pain substantially but not completely, because subjective side effects become troublesome. If higher doses were used regularly, patients would be excessively drowsy, nauseated, etc.”Study Details The double-blind, placebo-controlled, two-period, crossover trial included 30 ambulatory cancer patients recruited from tertiary care centers in Toronto and Sydney, who had persistent pain despite a stable regimen of strong opioids. Patients were receiving morphine (23 patients) or hydromorphone (7 patients) with median regular daily opioid doses in oral morphine equivalents of 200 mg (range of 20 to 2,100 mg). Half the patients were using corticosteroids and/or NSAIDs as co-analgesics. Analgesia was considered stable if no changes in either the opioid or non-opioid analgesics were required during the 48 hours before initiation of the study. Patients with predominantly neuropathic pain were excluded from the trial. Study subjects received 1 g of acetaminophen every four hours, five times a day, for 48 hours and an identical-appearing placebo on the same schedule for another 48 hours. The order (acetaminophen or placebo first) was randomly allocated by the study pharmacist. “The observed improvement [in pain and overall well-being in patients when taking acetaminophen] was small, real, and clinically important,” Dr. Stockler and his colleagues reported. While the improvements were small, in the range of 0.4 to 0.7 points on a 10-point scale, the averages included some patients who seemed to benefit a lot and some who did not seem to benefit at all. About one third of patients had improvements of one or more points, which the authors said are clinically important: “The people included were typical of ambulatory patients with cancer pain, and the results should be widely applicable.” Don't Adopt as Standard for All Patients Dr. Stockler said that while the addition of acetaminophen is worth considering in these patients, he does not recommend adopting it as standard for all patients. “There is little to be lost by trying acetaminophen for a few days,” he said. “If the patient feels better, and this outweighs the nuisance of swallowing more tablets, then I think it's worth continuing, but if not then it can be stopped.” Curiously, the researchers reported that study accrual overall was slow—in Australia because clinicians were reluctant to remove patients from acetaminophen treatment, and in Canada because clinicians were reluctant to use acetaminophen in such patients. “Heterogeneity of prejudice—and practice—is common and is an excellent rationale for a trial,” Dr. Stockler said. Commentary: Not Clear Why Pain Wasn't Better Controlled by the Opioids A US oncologist and palliative care specialist asked to comment on the study said it was not clear in the study why the pain was not better controlled by whatever opioid the patients were already on. “And the researchers said in general that side effects limit the dosing [of strong opioids] but didn't say specifically whether the side effects led them to consider adding the acetaminophen,” said Sonni Mun, MD, Chief of Medical Services at the Hertzberg Palliative Care Institute of Mount Sinai Hospital in New York City. Dr. Mun also said it might not be practical to prescribe yet another drug for patients already taking several per day. “Some clinicians are afraid of morphine, and this may be another article in which they try to offer an alternative, but any time you increase the frequency of taking a drug there is more chance of patients not being compliant,” she said. “It is a big deal to ask someone who is already taking medications five times a day to take another prescription.” Dr. Mun also noted that this was a small study and that it would be hard to say if the findings will be clinically born out. “At my institution, if the patient is already on morphine and their pain is not well controlled and there is no reason why you can't increase the morphine, simplicity makes the most sense,” Dr. Mun said. I would rather increase whatever medication they are already on. “I don't think it is wrong [to add acetaminophen in such cases] but it would not be convenient for a patient who is already taking a lot of different medications.” Coauthors, Meeting Abstract, Funding Dr. Stockler's coauthors were Janette Vardy, Avinesh Pillai, and David Warr. The study, which was presented in abstract form at three meetings last year (ASCO, the Medical Oncology Group of Australia, and the Clinical Oncology Society of Australia), was supported by a grant from the Cancer Council of New South Wales and Janssen Cilag, which makes fentanyl. The authors' disclosure of potential conflicts of interest indicated that there were none.

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