Our study found that patients receiving OAT exhibit significant alterations in pain perception, CPM, and wind-up, aligning with opioids’ known potential to paradoxically increase nociception in other settings. However, we take care to note that not all hyperalgesia arising during the course of opioid administration is necessarily ‘opioid-induced’. Taking this into account, our study demonstrates a strong association between OAT and changes in the pain pathways.

4.1 Central Sensitization

The International Association for the Study of Pain (IASP) defines central sensitization as an “increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input.” As direct electrophysiological recordings from central nervous system neurons cannot be performed in humans, the objective assessment of central sensitization in clinical practice is very limited. Clinical assessment typically evaluates surrogate parameters using two strategies. The first, quantitative sensory testing, relies on neurophysiological markers. Both mechanical and dynamic parameters, e.g. MPT, MPI, or TS , have long been recognized as pivotal measures of central sensitization [20, 21]. Supporting this, mechanical hyperalgesia has repeatedly been shown to increase in chronic pain conditions and has been proposed as a predictive tool for persistent postoperative pain [30]. The second strategy commonly used to evaluate central sensitization is the assessment of its clinical consequences and comorbidities, and it is this purpose for which the CSI was developed and validated; however, recent scholarship has demonstrated that these two approaches correlate only weakly [31]. When we designed the study, we took special care to integrate both different approaches for assessing central sensitization. Therefore, we included the CSI as a psychometric, self-report questionnaire, and quantitative sensory tests as neurophysiological parameters.

In our study population, we found that pain perception and markers of mechanical hyperalgesia differed significantly from previously published norm values; however, results from the CSI were divergent. Although 45% of participants indicated CSI values corresponding to at least mild central sensitization, the sample mean and norm values did not significantly differ.

4.2 Conditioned Pain Modulation and Wind-Up

Prior research has consistently demonstrated that increases in TS of pain and decreases in CPM are related to increases in clinical pain, in numerous chronic pain syndromes [32]. However, the possibility of impaired pain modulation due to prolonged courses of opioids (e.g., OAT) is seldom addressed, and the existing evidence is in conflict [33, 34]. With respect to OAT, a recent literature review critically noted that no data on CPM or dynamic parameters in this unique population can be found [35]. We showed that both CPM and wind-up are severely altered among patients receiving OAT, in comparison with published norm values.

4.3 Dose-Response Relationship

The prior literature includes only sporadic investigations of the possibility of a dose-response relationship between high-dose opioids and alterations of the somatosensory system. In the context of OAT, these scarce descriptions are limited to case reports [36,37,38]. To the best of our knowledge, our data are the first to demonstrate a dose-response relationship between high-dose opioids and markers of central sensitization in an observational study.

The dose-response relationship of CPM is particularly interesting in light of conflicting literature [34, 39]. Our data illustrate a moderate relationship between CPM and opioid doses in OAT; however, when interpreting our results, it is pivotal to consider the heterogeneity of our study population and the potential influence of variables, such as the timing of OAT intake, which we have neither assessed nor stratified.

4.4 Population

The need for epidemiological data on opioid-related alterations of pain perception and hyperalgesia in special populations has only recently been articulated [40]. Existing clinical knowledge of OIH is largely limited to the perioperative period. Apart from the fact that these studies were mainly conducted with remifentanil, fentanyl, or sufentanil, which are rarely administered beyond the perioperative phase, tissue trauma per se can lead to sensitization and may therefore confound attempts to measure the contribution of opioids to hyperalgesia.

Very few studies have examined OIH in patients receiving protracted opioid therapy for chronic pain. Of these, many are either conducted with relatively low opioid doses or do not address the dose range at all [32, 41, 42]. Furthermore, chronic pain is often accompanied by somatosensory system alterations, which complicate the interpretation of the effect possibly attributable to opioid therapy.

In patients receiving OAT, these confounders are absent. This population also boasts a second important difference—the use of high-dose opioids often well in excess of the doses typically applied for analgesic purposes. Despite these advantages, few reliable studies have explored the effects of opioids on the pain pathways in this population, and those that do have not reported doses comparable with those in our study.

4.5 Substances4.5.1 Morphine

Previous studies focused on pain pathway changes during OAT were primarily conducted with buprenorphine or methadone. Data pertaining to patients receiving high-dose morphine as OAT could only be extracted from a small number of case reports [3, 43]. Austria is one of the few countries in which extended-release morphine is used for OAT [2], and, in our sample, over three-quarters of patients are receiving this agent. The present study is therefore uniquely positioned to offer the first large-scale observational report on the effect of OAT with extended-release morphine on changes of pain pathways.

When comparing the effects of the various substances used for OAT in our sample, we did not observe significant differences; however, it must be taken into account that some of these are represented by only a small number of patients, limiting statistical power in the comparison.

4.5.2 Co-Medication

Only 8 (6.7%) participants in the study were concurrently taking a medication with the potential to influence the development of hyperalgesia (e.g., ketamine, antidepressants, anticonvulsants, magnesium). With so few patients receiving co-medication, we were unable to demonstrate any significant association with our observed outcome parameters.

4.6 Measurement Parameters

A recent systematic review identified the common lack of assessment of both pain threshold and pain tolerance in patients with chronic opioid exposure [44]. The methodology used to record pain thresholds is fundamentally relevant to the interpretation of the results; this study’s meta-analysis revealed that cold stimuli were commonly used [44]. This fact could be criticized in view of the fact that heat and mechanical pain, but not cold stimuli, are generally regarded as surrogates for peripheral and central sensitization [45], and their application may have superior validity for the detection of hyperalgesia. Thus, our study has explored the effects of high-dose OAT on changes of pain pathways using the former set of measurement parameters.

4.7 Limitations

Although we have identified several strengths of the present study’s design, some limitations exist that effect the interpretability of our results. First, morphine is the predominant substance in our study population, which limits the applicability of our findings to other settings where morphine is not used for this indication. Morphine is however still considered the reference substance among opioids and therefore these results are of high value, especially since no data with comparably high doses exist.

Other OAT substances are less well-represented in the present study. Although we aimed for a sensitivity analysis, the low number of participants with OAT excluding morphine unfortunately rendered it impossible.

Another limitation is that due to the cross-sectional design, the results of our study are unable to make claims regarding changes of pain pathways as a function of time receiving OAT. However, including this longitudinal aspect was not feasible in the present study design, and will be an intriguing component of future research, especially in patients for whom the dose is tapered over time.

The conversion ratios of the different opioids to oral MME was based on a publication in patients receiving OAT for OUD [18]. These data differ from conversion rates used in acute and chronic pain medicine; however, we decided to use these specific ratios as they are the population closest to ours in terms of indication and dosage. The mean MME in their study ranged between 626 and 922 mg/day and was therefore in the range we observed in our sample. We did however not take dosing time points and timing of intake into account. Although OAT is applied as an extended-release formulation, there are relevant circadian changes in plasma concentrations [46]. In our institution, patients take their OAT in the morning, with the testing taking place around midday and therefore presumably at peak level. As we have not specifically assessed the timing, we cannot rule out a temporal effect.

Likewise, we may have not included other potential confounding variables, including information regarding the co-occurrence of various non-opioid substance use disorders. For smoking, for example, an interdependency with pain perception is frequently reported [47]. Assessing data on addictive behavior is however a methodological challenge, with a great chance of misinformation [48]. We have therefore not included these issues in our questionnaire; however, we cannot rule out that these factors are relevant contributors or confounders.

4.8 Clinical Application and Future Directions

Our results contribute to the understanding of pain experience and modulation among patients receiving OAT and may be generalized to other populations receiving high-dose opioids. Previous work has shown that pain management is a major source of morbidity and quality-of-life reductions among patients with OUD. Our results offer a possible avenue of enhancing pain management for these patients, clearly identifying two main contributors to somatosensory system alterations—central sensitization leading to an amplification of nociceptive input, and simultaneous impairment of the descending pain system causing reduced pain inhibition. Taken together, these factors explain how patients receiving high-dose opioids may experience relevant pain from nociceptive signals that are otherwise perceived as relatively benign stimuli. This corresponds to the clinical definition of hyperalgesia and suggests that therapeutic approaches focusing on the mitigation of these hyperalgesic effects and the augmentation of endogenous pain inhibition systems will be useful tools for the optimization of pain management in patients receiving high-dose opioids.