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Morphine more effective than weak opioids for cancer-associated pain
Low-dose morphine significantly reduced pain intensity compared with weak opioids in patients with cancer, according to results of a randomized controlled trial.
The effects of low-dose morphine took effect earlier than opioids, and the regimens appeared comparable with regard to tolerability.
WHO guidelines on palliative care for patients with cancer recommend a sequential three-step analgesic ladder, beginning with nonopioids and continuing to weak opioids and strong opioids. Prior research has not established whether patients with moderate pain should receive weak opioids or low-dose strong opioids.
Mario Luppi, MD, PhD, professor of clinical and experimental hematology at University of Moderna and Reggio Emilia in Italy, and colleagues conducted a randomized, controlled open-label study to compare weak opioids with low-dose morphine in patients with cancer who reported moderate pain levels.
The analysis included 240 opioid-naive patients (median age, 68 years; range, 58-74) assigned to oral morphine (n = 118) or weak opioids (n = 122) for 28 days. The majority of patients assigned weak opioids (n = 103) received a fixed combination of codeine (n = 99) or tramadol (n = 4) plus paracetamol; the remaining patients (n = 19) were assigned tramadol alone.
The number of responding patients — with response defined as a 20% reduction in pain intensity on the numerical pain rating scale (NRS) — served as the primary endpoint.
Significantly more patients assigned low-dose morphine achieved the primary endpoint (88.2% vs. 57.7%; OR = 6.18; 95% CI, 3.12-12.24).
The researchers observed a higher rate of response among patients assigned morphine as early as 1 week after initiation (80.9% vs. 43.6%; P < .001).
Clinically meaningful (≥ 30%) and highly meaningful (≥ 50%) pain reduction from baseline occurred at significantly higher rates in the low-dose morphine arm (P < .001).
By the end of the observation period, both groups registered satisfactory pain control, although with a statistically and clinically significant advantage among those assigned morphine (median NRS score, 1; interquartile range [IQR], 0-2) compared with weak opioids (median NRS score, 2; IQR, 0-4; P = .02).
Changes to assigned treatment occurred more frequently in the weak opioid arm due to inadequate analgesia, and the general condition of patients — determined using the Edmonton Symptom Assessment System overall symptom score — appeared better in the morphine arm.
Both treatment regimens appeared well tolerated. Ten patients ― five in each study arm ― discontinued treatment due to adverse events or poor tolerability.
The intensity and frequency of opioid-related symptoms did not differ between study arms.
The researchers acknowledged the open-label study design, as well as the low patient accrual, as potential limitations.
“The current WHO recommendation has the three-step pain ladder as the basis for treatment of cancer pain,” Luppi and colleagues wrote. “New guidelines, including that by the European Association for Palliative Care, describe a two-step approach as an alternative. To abolish the second step will simplify treatments and perhaps give patients with cancer better pain control. Whether the findings of this study, which are in favor of starting directly with a step three opioid, may contribute to changing the WHO guidelines must be confirmed by other phase 3b/phase 4 studies.” – by Cameron Kelsall
Disclosure: Luppi reports no relevant financial disclosures. Other researchers report travel expenses from Astellas, BiParSciences/Sanofi, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Exelixis, GlaxoSmithKline, Janssen, Merck, MSD, Novartis and Roche, as well as consultant roles with Amgen, Norgine, Otsuka and Teva.
Perspective
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Effectively palliating cancer pain is a central responsibility of the oncologist. Recognizing which opioids are most effective and how best to approach their associated adverse events ensures effective pain management.
WHO guidelines regarding cancer pain management are a sequential, three-step ladder approach. It suggests the first (NSAIDs, acetaminophen) and second (codeine, tramadol, or combination opioid/acetaminophen products) steps should be used before the third (opioids). This approach implies that the first and second steps are safer and that opioids should be reserved for severe pain. Given the analgesic ceiling effect and associated side effects of NSAIDs, is this true?
Bandieri and colleagues address a key issue relevant to the oncologist — the efficacy of weak opioids (such as tramadol with our without paracetamol or codeine with or without paracetamol) vs. low-dose morphine in patients with moderate cancer pain. Patients experienced clinically meaningful pain reductions in shorter time with morphine. Further, there was no difference in the intensity and frequency of opioid-related side effects between morphine and weak opioids.
The results of this study challenge the WHO sequential approach to moderate cancer pain and reintroduce an established, effective tool: morphine. Strong opioids such as morphine have been the mainstay of cancer pain management for decades and no study to date has shown that morphine is ineffective or causes harm when prescribed appropriately. Despite this, patients still fear morphine given its associations with misuse, abuse and death. Patients also incorrectly attribute anticipated adverse effects — such as nausea, pruritus and constipation — as true allergies, limiting the use of this effective, cost-efficient opiate.
The implications of this study provide us with an opportunity to reengage and reeducate our patients regarding the established efficacy of morphine. When patients express concerns about its use, we should inquire, teach and use prophylaxis for anticipated adverse events such as constipation and nausea. Effectively treating cancer pain ensures we can aggressively treat the underlying cancer while optimizing the quality of life of our patients.