New Perspectives on the Adverse Effects of NSAIDs in Cancer Pain: An Italian Delphi Study from the Rational Use of Analgesics (RUA) Group^†

Round 1

Reviewer 1 Report

The study is fine, methods are written in detail, data is convincing, article reads good throughout the manuscript.

As the study is on the “adverse effects of NSAIDs in cancer pain”; out of 21 statements formulated only 1 statement has mentioned cancer pain. I assume that all the participants are clearly aware of the focus of the study while voting for the statement?

The study Giustino Varrassi1et al has clinical significance in managing pain in cancer patients and adverse effect of NASIDs to improve their quality of life and minimized the side effects.

The materials and methods section of the manuscript is written in detail, which improved the quality of the manuscript.

Author Response

Reviewer #1

1. As the study is on the “adverse effects of NSAIDs in cancer pain”; out of 21 statements formulated only 1 statement has mentioned cancer pain. I assume that all the participants are clearly aware of the focus of the study while voting for the statement?

-Thank for pointing out the issue, I would like to assure the reviewer that all the members of the advisory board were aware of what was being discussed was cancer pain. Furthermore, we believe that the adverse effects are similar, independently of the type of pain; so, in only one statement, cancer pain was clearly indicated.

Reviewer 2 Report

The paper is interesting and highlights the difficulties in treating pain, especially chronic pain, faced by patients around the world despite the presence of so many painkillers. The work is well structured and the purpose clearly explained. However, the work is not super revealing, it rather shows what is already known. I have some concerns as follows:

      It should be emphasized that paracetamol does not belong to NSAIDs. Paracetamol is an alternative to NSAIDs (peptic ulcer, allergic to NSAID, bleeding disorder) but does not have anti-inflammatory potency (45-46 line). It should be explain why paracetamol was included in the study.

2.     The description of the analgesic pain ladder should be described in more details. It should be stressed that the polytherapy is recommend in the management of chronic pain. A much better analgesic effect will be achieved if we combine two painkillers with two different mechanism of action (e.g. NSAID+paracetamol or opoid+pregabalin/gabapentic/SNRI/NSAID/paracetamol) than we will increase the dose of one drug.

3.     Diagnosis is also very important in the treatment of chronic pain. Is it neuropathic or pathological nociceptive pain? NSAIDs are effective only in the latter, which results from their mechanism of action (inhibition of prostaglandin synthesis). NSAIDs are very often prescribed or used as OTC drugs in neuropathic pain and it is mistakenly interpreted as “not being effective”. Probably this is the answer for one of the statement for which consensus was not reached:

“NSAIDs are not appropriate for the long-term treatment of chronic inflammatory pain, as they mainly act on peripheral inflammatory processes. NSAIDs act as peripheral anti-inflammatories and are not indicated for chronic pain” - What kind of chronic pain do the authors of the publication mean – perhaps neuropathic pain? In neuropathic pain NSAIDs are ineffective – In my opinion this is the problem of wrong diagnosis of the pathophysiology of pain.

Overall, the work is of interest for different aspects related to management of chronic, cancer pain and may represent a valid contribution to daily practice.

Author Response

Review # 2

1.It should be emphasized that paracetamol does not belong to NSAIDs. Paracetamol is an alternative to NSAIDs (peptic ulcer, allergic to NSAID, bleeding disorder) but does not have anti-inflammatory potency (45-46 line). It should be explained why paracetamol was included in the study.

In the Introduction, now, the analgesic, non-anti-inflammatory paracetamol properties have been underlined.

2.The description of the analgesic pain ladder should be described in more details. It should be stressed that the polytherapy is recommend in the management of chronic pain. A much better analgesic effect will be achieved if we combine two painkillers with two different mechanisms of action (e.g., NSAID + paracetamol or opioid + pregabalin/gabapentin/SNRI/NSAID/paracetamol) than we will increase the dose of one drug.

Thanks to point out this issue: we underline, at the end of Introduction, how difficult is to correct recognize and manage pain related to malignancies.

3.Diagnosis is also very important in the treatment of chronic pain. Is it neuropathic or pathological nociceptive pain? NSAIDs are effective only in the latter, which results from their mechanism of action (inhibition of prostaglandin synthesis). NSAIDs are very often prescribed or used as OTC drugs in neuropathic pain, and it is mistakenly interpreted as “not being effective”. Probably this is the answer for one of the statements for which consensus was not reached.

Thanks again for this intriguing issue; it is difficult to correctly understand nature of cancer pain, due probably both to cancer and anti-cancer treatment. We report these difficulties in the Introduction paragraph. Unfortunately, Delphi method doesn’t help us in understanding the reasons because a statement has not reached the consensus, leaving the answer open to future studies.

4. “NSAIDs are not appropriate for the long-term treatment of chronic inflammatory pain, as they mainly act on peripheral inflammatory processes. NSAIDs act as peripheral anti-inflammatories and are not indicated for chronic pain” - What kind of chronic pain do the authors of the publication mean – perhaps neuropathic pain? In neuropathic pain NSAIDs are ineffective – In my opinion this is the problem of wrong diagnosis of the pathophysiology of pain.

The reviewer is most likely true because the difficulties in the diagnosis of cancer pain: the aim of our work was to suggest, during the daily practice, the right approach even considering adverse effects.