*3.4. The Indications Detailed in the Self-Reported Opioid Prescribing Behavior*

Physicians most often reported that their opioid prescription was for the following diagnoses: disc prolapse (62%) and grade 3 and 4 pressure ulcers (60%); the national LONTS guideline specifies an open recommendation for these (Table 3). Osteoarthritis was the most common indication (56%) that physicians reported prescribing strong opioids, for which the LONTS guideline provides an evidence-based positive recommendation for short-term (4–12 weeks) and immediate-term (13–26 weeks) use (Table 3). For chronic nonspecific low back pain, 38% of physicians reported prescription rates of strong opioids, for diabetic polyneuropathy 41% and for postherpetic neuralgia 38%, which follows positive (short-term use) or open guideline recommendations (long-term use) (Table 3). Although for the following diagnosis, the LONTS recommendations are negative (Table 3), 42% of physicians reported prescribing strong opioids in chronic inflammatory bowel disease, 30% in chronic pancreatitis, 26% in functional disorders, 25% in fibromyalgia syndrome and 20% in primary headaches.


**Table 3.** Indications of physician self-reported opioid prescribing behavior compared to guideline recommendations.


<sup>a</sup> does not apply = physician has not treated patients with this disease in the past 12 months; <sup>b</sup> German guideline for long-term use of opioids in chronic noncancer pain; <sup>c</sup> recommendation for radiculopathy.

#### *3.5. Physicians' Self-Reported Emotional Reactions to Patient Requests to Increase Opioid Dosages*

The feeling of being well-equipped to handle a patient's request of increasing the opioid dosage to treat unspecific low-back pain was reported by 59% of the physicians, whereas 43% of the physicians described negative feelings in such a situation. About one quarter of the physicians expressed feelings of either pressure (25%), helplessness (25%), anger, or a combination (23%) (Table 4). A smaller subgroup of physicians reported that despite negative feelings they can handle the situation quite well: 59 physicians reported anger and good management of the situation (10% of the whole group); helplessness and good management of the situation was reported by 32 physicians (5% of the whole group) (Figure 2).

**Table 4.** Physician self-reported emotional reactions to a patient's desire to increase opioid dosage in long-term opioid therapy of chronic unspecific low back pain.


**Figure 2.** A selection of physician self-reported emotional reactions to a patient's desire to increase opioid dosage and their overlaps.

#### *3.6. Covariate Analysis of Non-Guideline-Compliant Opioid Prescribing Behavior*

Physicians prescribing ultrafast-acting fentanyl formulations were also highly likely to prescribe sublingual buprenorphine (OR: 15.4; 95%-CI: 10.1–23.3; *p* < 0.001). The presence of negative emotions in response to patients' demands for a dose escalation nearly doubled the likelihood of physicians to prescribe ultrafast-acting fentanyl to their patients (OR: 1.7; 95%-CI: 1.2–2.6; *p =* 0.007). Other aspects, such as work experience or risk literacy, were not found to be associated with physicians' prescription behavior. The final independent variables included in the binary logistic regression analysis (Table 5) increased the proportion of correctly predicted answers from 51.0% to 78.5%. The selected model explains 41% of the existing variance (Nagelkerkes R-Quadrat).

**Table 5.** Binary logistic regression analysis with non-guideline-compliant opioid prescribing (ultrafastacting fentanyl for CNCP) as dependent variable.


<sup>a</sup> as reaction to the case study vignette relating to a patient request for an opioid dose increase.

#### **4. Discussion and Conclusions**

This analysis of the ERONA study showed that physicians in Germany reported a prescribing behavior for strong opioids for CNCP that was not consistently compliant with current guidelines—both in terms of opioid indications and the opioid formulations selected. A bad feeling about increasing an opioid dose in a situation without objective signs of deterioration was reported by 43% of the physicians surveyed. Emotions such as pressure, helplessness and anger were reported by 25%, 25% and 23% of the physicians in this situation. Perceived negative feelings about an opioid increase were associated with more non-compliant prescribing behavior.

The LONTS guideline, based on controlled clinical studies, recommends opioid prescription at least for 4–12 weeks for the following four diagnoses: chronic nonspecific low back pain [27], osteoarthrosis [28], diabetic polyneuropathy and postherpetic neuralgia [29]. The prescribing behavior of the physicians surveyed in our study indicated that they prescribe strong opioids most frequently for osteoarthritis (OA) (56%), and less often for chronic nonspecific low back pain (CLBP) (38%) (Table 3). This corresponds to the recommendation of the National Guideline for CLBP [30], which specifies opioids may be a short-term option only for selected patients. Comparing treatment guidelines for OA and CLBP, psychosocial factors seem to be more prominent in CLBP than in OA, where they certainly also play a role, but the somatic pain component is usually in the foreground [31,32]. In addition, OA pain often affects older people, where other therapy options, such as NSAIDs, are often either contraindicated [33], exercise therapy is more limited [34], or both.

The opioid prescriptions by physicians in this study for functional disorders, fibromyalgia syndrome and primary headaches appeared problematic, and they were anticipated to have negative consequences for the patient, such as unwanted medication overuse, headache (MOH) [12] or problematic opioid use. Prevalence data on the use of opioids in functional disorders are difficult to define since various heterogeneous diseases are collated under this diagnosis.

Further, immediate-release opioids are seldom necessary for noncancer pain [13] and ultrafast-acting opioids are exclusively licensed for cancer pain [35]. The fact that we found 49% of physicians in our study prescribing ultrafast-acting fentanyl to CNCP can be considered highly problematic. The challenge of non-indicated "off-label-use" has been described previously [36,37] and has been observed in other cohorts, for instance among Italian patients with CNCP of which nearly 10% received ultrafast onset opioids [38]. Training, education and the implementation of prevention strategies—possibly including either medico-legal consequences, non-reimbursement by the health insurance companies or both—would be necessary measures to restrict such misuse [39].

The role of sublingual buprenorphine, on the other hand, must be seen in a differentiated manner. It has a significantly longer onset and action time than fast-acting fentanyl. It is also approved for non-cancer pain, unlike the rapid-acting fentanyl preparations. In this respect, we were surprised by the fact that physicians who prescribe sublingual buprenorphine, which can be indicated in CNCP, were 15 times more likely to also prescribe fast-acting fentanyl, which is not indicated in CNCP. Perhaps these figures expressed the fact that those physicians were well versed in handling a wide variety of preparations and galenics. However, even within this group, there were those who adhere to the indications and others that do not.

In our study, 43% of the physicians reported a negative emotion associated with their own responsibility to a dose elevation in response to a patient's demand to increase opioid dosage without any obvious deterioration. Our study documented—to the best of our knowledge, for the first time—that such negative emotions may significantly influence physicians' reaction to these demands: Physicians presenting with negative emotions tended to exemplify more non-guideline-compliant behavior than did those who did not report such negative emotions. Not having negative emotions appeared to protect physicians from prescribing and patients from receiving an opioid medication that is not indicated for noncancer chronic pain. These findings on the role of negative emotions on patients' potentially unwarranted demand for dosage increase has been seldom described until now. However, it was in line with the prescriber style described by Passik et al., which is, for example, characterized by "aggressive opioid titration [ ... ] with intents to entirely eliminate pain." [40]. It is of course also conceivable that negative gut feelings warn against an unjustified prescription.

Considering the consequences of non-compliant prescriptions of potent but risky drugs for patients' safety, the currently rather under-studied influence of different negative emotional states on physicians' compliance to guidelines certainly requires more research on these aspects to inform curricula and continuing training programs on appropriate opioid prescriptions.

Our study had some limitations. A critical point of this study was the high nonresponse rate during the recruitment process because the remaining physician cohort may not be representative of physicians working in Germany. At first glance, for example, women seemed to be underrepresented. However, if one compares the proportion of women in our study with the data of the German Medical Association (GMA) [41] based on the six most frequently occurring groups of expertise in this study, the proportion is 37% compared to 40% (GMA), thus only a little bit lower. If it was considered that older and more experienced physicians answered this survey, our data appeared to be quite representative in this point since the proportion of women is lower in the group of older physicians. The external validity of this study of course remains a critical point. For example, physicians may have responded who are already more critical of their prescription of opioids or more aware of their feelings than others. However, the focus of this study should be to draw attention to the presence of emotional aspects of opioid prescription and not to claim that the numbers determined were absolutely correct.

Another limitation was that these data are only based on self-reports, which may invite inaccuracies due to social desirability. Questions may have been misunderstood, e.g., that the addition "for noncancer pain" was missed in the questions about opioid preparations. We hoped to have minimized such issues by piloting material with colleagues. A further limitation is that we did not know how frequently non-guideline-compliant prescriptions occurred, as we have no information about the patients actually seen in these practices and the rates of prescription. Another inherent limitation was that the current study showed only an association between negative emotions and prescribing behavior rather than a cause-and-effect relationship. It could be, for example, that physicians' overprescribing was

leading to a feeling of helplessness and anger, but it could also be that their initial feeling of anger and helplessness was leading to overprescribing. Other study designs, especially either qualitative designs, longitudinal quantitative designs or a combination, should investigate these questions. Another important point is that the questions concerning the emotional reactions of the physicians are not a part of a validated questionnaire. This reduces the internal validity of the results. After a qualitative scientific examination of the topic "physicians' emotions and prescribing opioids" as suggested above, the goal should be to generate a validated questionnaire that serves both research purposes and routine use to sensitize physicians to this topic.

This analysis showed that in Germany strong opioids are largely prescribed in accordance with the existing guidelines. However, there were indications where the use of opioids should be viewed critically, e.g., in the case of primary headaches, fibromyalgia syndrome or other functional pain syndromes. Fast-acting fentanyl preparations should not be used in CNCP. Emotional aspects on the part of the prescribing physician could also play a role if opioids are not prescribed in accordance with the guidelines.

**Supplementary Materials:** The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/jcm11092506/s1, Project: ERONA—Physicians.

**Author Contributions:** O.W. conceived the project and was involved in preparing the manuscript; E.S. and N.D.-B. were involved in planning the study; E.S. analyzed the data and drafted this manuscript; O.W., R.H. and C.S. secured the funding for the project; O.W., C.S. and R.H. supervised the project; F.P., C.D., N.D.-B., M.S., C.S. and O.W. reviewed and edited the manuscript. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work is supported by the German Federal Ministry of Health (BMG) (grant number: 2519ATS001).

**Institutional Review Board Statement:** Institutional Ethics Board of the Max Planck Institute for Human Development, Berlin (Germany); Ethic Approval ID for pilot test: A 2019-32; for RCT and cross-sectional study: A 2020-05. Clinical trial number: DRKS00020358.

**Informed Consent Statement:** Informed consent was obtained before starting the survey.

**Conflicts of Interest:** See ICMJE form for Conflicts of Interests declared by CS. All other authors declare no competing interests.
