4. Discussion
neuropathic pain, illness, Pain, anxiety, toxicity, pain, PHN, head and neck cancer, nonpain, peripheral neuropathic pain, chronic pain, IASP
PHN, ADVERSE EVENTS, RECRUITMENT, HEAD AND NECK CANCER, CHRONIC PAIN, DRUG-DRUG INTERACTION
A majority of patients with neuropathic pain suffer from LNP. Based on the International Association for the Study of Pain (IASP), LNP is described as a type of peripheral neuropathic pain characterized by consistent and circumscribed area(s) of maximum pain associated with abnormal sensitivity of the skin and/or spontaneous symptoms characteristic of neuropathic pain [Regarding the initiative on methods, measurement, and pain assessment in clinical studies, several outcome measures, corresponding to six domains, have been recommended for assessment in pain trials: (1) pain, (2) physical functioning, (3) emotional functioning, (4) participant ratings of improvement and satisfaction with treatment, (5) symptoms and adverse events, and (6) participant disposition. However, since many treatments often only provide meaningful pain reductions in 40%–60% of patients, other outcomes such as physical, social, and occupational function are sometimes considered to have comparable importance [However, the results of the preliminary literature review on LNP revealed a lack of conclusive research concerning topical therapeutic options. A limited number of studies discussed and compared the efficacy of each of the topical treatments with that of a placebo. However, a 2014 systematic review of topical lidocaine for neuropathic pain (involving 280 patients with PHN) showed very low-quality evidence of the efficacy of topical lidocaine owing to small sample size, incomplete outcome assessments, and modest outcome measures of efficacy. Other clinical trials have found that 5% lidocaine patches are effective and well-tolerated for treating PHN with minimal toxicity risk or drug-drug interactions [The capsaicin dermal patch delivers a high concentration (8% w/w) of synthetic capsaicin, a highly selective agonist of transient receptor potential vanilloid-1 (TRPV-1), directly to the site of pain. The 8% capsaicin dermal patch is indicated in the European Union (EU) for the treatment of peripheral neuropathic pain in adults, either alone or in combination with other medicinal products [Considering the current lack of solid scientific evidence, the findings of the PELICAN study would have provided valuable and unique information regarding the comparison between systemic and topical medications. Despite the extensive preparation and review of the final study protocol, the PELICAN study had to be discontinued due to the low recruitment rate. Some possible primary causes were revealed during the qualitative study, but it is also necessary to critically assess the reasons for the termination of the PELICAN study considering the observed findings in other unsuccessful studies.Failure to enroll sufficient participants in a trial has been a long-standing problem [In the PELICAN trial, recruitment appeared slow from the outset and relied primarily on internal referrals (within the participating hospitals). Although educational material and flyers were kept at the disposal of the pain centers, it remained difficult to substantially increase the volume of internal referrals in all participating centers. In addition, the study team quickly observed that almost no patients were referred to the participating pain centers by primary care practitioners. It is commonly known that most chronic pain patients are treated by GPs. The previously mentioned large-scale European pain survey by Breivik et al. indicated that most pain patients (70%) are treated by GPs and 27% by an orthopedic specialist. Only 2% of chronic pain patients were treated by a pain management specialist. Most respondents (69%) had been treated by the same physician for 1–15 years. When explicitly asked whether they had ever been to a pain management specialist, 23% of patients (mean) responded affirmatively. This percentage, however, differed significantly throughout Europe, ranging from 8% in Norway to 40%–43% in France, Israel, and Italy. It is obvious that every pain-related study must involve GPs in the inclusion of patients and to enable timely referral of sufficient numbers of pain patients. Failure to actively involve GPs in the design and execution of the study protocol will significantly compromise a successful recruitment strategy.Efforts were made to address the recruitment issues: a substantial number of GPs in all geographical parts of Belgium received a letter explaining the trial, patient flyers were provided for the waiting room, the trial was made public via a website and social media, and the study team presented the PELICAN study on different occasions to both pain and nonpain colleagues. Unfortunately, none of these efforts had the desired results since no impact could be observed on the recruitment rate.After discussing this lack of recruitment with the participating clinics' representatives, the PELICAN study team revised the target sample number. The feasibility report elaborated on each center's capability to recruit patients and the period needed to accomplish this. Later, the report was discussed again with the investigators, who agreed on the selected target, yet the slow recruitment rate still did not improve. Thus, there was a considerable gap between the actual and intended patient numbers. Therefore, overestimation could have played a role in this study. It is crucial to properly understand how large the corresponding patient population is, how many people are needed in this population, and how many will participate. This is where many investigators overestimate the number of patients to be ultimately included in their trial [The inclusion and exclusion criteria are important for the reliability of medical trials. Very restrictive criteria cause willing patients to be excluded for not fulfilling the trial's essential criteria. Likewise, some of the inclusion and exclusion criteria applied in the PELICAN study may have affected the number of patients included in the study. It became evident that pain duration was often prolonged in patients who were prescreened for inclusion in the PELICAN study. Unfortunately, this is in accordance with general epidemiological findings. Breivik et al. showed that only 12% of respondents have suffered from pain for <2 years, almost 60% between 2 and 15 years, and many (21%) had lived with pain for ≥20 years, with an overall median pain duration of 7.0 years [Another protocol-related criterion that negatively impacted recruitment was related to the exclusion of previous treatment with gabapentinoids. This proved to be especially critical as the study started from pain management clinics and not from general practices. Considering the common treatment trajectory of patients with pain, many had already been introduced to analgesics and antineuropathic drugs and were therefore no longer eligible for enrollment. Primary care physicians are accustomed to using anticonvulsant drugs in patients with suspected neuropathic pain conditions. Due to the restrictive nature of the study protocol, even a short-term trial therapy with an anticonvulsant immediately resulted in exclusion from the PELICAN study, even if no topical treatment had previously been tested. In the future, one should consider implementing changes to the inclusion criteria for analgesic trials so that short-term negative trial treatments can be discarded based on several predetermined criteria such as duration of trial treatment, the maximum dose administered, and occurrence of side effects. Such an approach would increase the number of patients eligible for inclusion in the study protocol.We should ask ourselves whether recruitment failure could have been prevented. Briel et al. stated that the most common reasons for recruitment failure seem preventable in a pilot study that applied the planned informed consent procedure [Another reason for recruitment failure in the PELICAN study could be linked to the irregular medical follow-up by chronic pain patients. This was mentioned in several interviews during the qualitative study and is confirmed by the findings of previous studies. Breivik et al. in their European survey on chronic pain delved more closely into the number of patients' visits to doctors. The interviewers asked participants how many times in the last 6 months had they visited their primary treating physician for their illness or medical condition that caused pain. Reportedly, 16% had not visited their physician at all, 14% had visited only once, 60% had visited two to nine times, and 11% had visited at least 10 times in the last 6 months. Of the respondents, 35% had consulted one single physician, while 54% had consulted two to six different physicians during the same time frame [Several concerns were raised regarding several digital aspects of the study. Digital health has become more important, especially since the COVID-19 pandemic, but it should be implemented with a lot of considerations for patients as well as for the supporting study staff. Half of the responders from the participating pain centers believed that using the digital platform for the follow-up of the therapeutic response and adverse events caused anxiety in some patients or even dissuaded them from (further) participation. This feedback is of major concern for the study team and is somewhat unexpected since the application of a similar digital platform in previous pain-related studies was well received by patients [Patients may experience out-of-pocket costs when participating in a clinical study, including transportation costs and lost work as well as medical costs for additional testing or interventions. Insurance or social security may not cover medical care beyond what is deemed evidence based. Even when medical care is covered, deductibles are often relatively high, and a patient may not be able to afford participation. Notably, patients' fear of having to pay for the costs themselves after the study ends significantly hampered their willingness to participate in clinical trials [One additional comment should be made regarding the capsaicin treatment that could have negatively impacted patients' willingness to participate in the trial. Patients are unfamiliar with capsaicin as a therapeutic agent [Investigators should also carefully consider which study method is the most appropriate to obtain the necessary information. Qualitative surveys, like the one we performed, are an often-used possibility, but one should also consider the performance of Delphi studies. Surveys have been performed in several countries to investigate some major pain-related issues [Finally, there is also some critical discussion outlining the role and possible benefits of social media in augmenting and supporting the original methods of recruitment. Reuter and Lee investigated this matter and concluded that, mostly, social media has complemented rather than replaced traditional recruitment efforts [All the abovementioned findings are essential to be taken into consideration in future pain studies. Given the extremely low number of drugs currently approved for pain treatment, it is crucial to address all barriers to recruitment to allow new therapies to be successfully validated in completed clinical trials. For instance, the same remarks have been formulated for studies related to head and neck cancer [On the positive side, the topical administration of capsaicin has become more widely known within pain centers because of their participation in the PELICAN study. Moreover, in half of the participating pain centers, participation in the PELICAN study was used to facilitate the clinical diagnosis of LNP.